Urethane-crosslinked biodegradable elastomers

ABSTRACT

Among other things, the present disclosure provides compositions and methods for an elastomeric cross-linked polyester material. Such an elastomeric cross-linked polyester material, in some embodiments, comprises a plurality of polymeric units of the general formula (-A-B-)p, wherein p is an integer greater than 1; and a plurality of urethane cross-links each of which covalently links two polymeric units to one another, which two linked polymeric unit each had at least one free hydroxyl or amino group prior to formation of the crosslink.

RELATED REFERENCES

This application is a continuation of pending prior U.S. applicationSer. No. 17/185,528, filed Feb. 25, 2021, which is a continuation ofU.S. application Ser. No. 16/024,560, filed Jun. 29, 2018, now U.S. Pat.No. 10,982,038, issued Apr. 20, 2021, which is a continuation of U.S.application Ser. No. 13/594,834, filed Aug. 26, 2012, now U.S. Pat. No.10,035,871, issued Jul. 31, 2018, which claims the benefit of andpriority to U.S. provisional patent application Ser. No. 61/527,879,filed Aug. 26, 2011, the entire contents of which are hereinincorporated by reference.

GOVERNMENT SUPPORT

This invention was made with government support under Grant Nos.DE013023 and GM086433 awarded by the National Institutes of Health, andunder Grant No. BES0609182 awarded by the National Science Foundation.The government has certain rights in this invention.

BACKGROUND

Biodegradable elastomers have emerged as promising materials for theirpotential to mimic the viscoelastic properties of several tissues andexhibit compliance with dynamic environments without damaging thesurrounding tissue. However, there remains a continuing need for newsuch biodegradable elastomer materials. In particular, the developmentof highly tunable biodegradable elastomers that can effectively andcontrollably present biological and physical signals and withstandrepeated cycles of physiologic loads, has remained elusive.

SUMMARY

In various aspects, the present disclosure provides elastomericmaterials (e.g., biodegradable elastomers), compositions containing them(e.g., precursor compositions), and methods for their production anduse. In particular, the present invention provides compositionscomprising a polyester material together with and/or crosslinked by apolyisocyanate crosslinker. The present invention therefore provideselastomeric materials that include at least one urethane crosslinkcovalently linking polymer components within the material to oneanother.

In some embodiments, an elastomeric cross-linked polyester materialcomprises a plurality of polymeric units of the general formula(-A-B-)_(p), wherein p is an integer greater than 1; and a plurality ofurethane cross-links each of which covalently links two polymeric unitsto one another, which two linked polymeric unit each had at least onefree hydroxyl or amino group prior to formation of the crosslink,wherein each (-A-B-) polymeric unit has a chemical structure that isachieved when a polyol component A′ is condensed with a polyacidcomponent B′, so that each -A- component represents a substituted orunsubstituted ester and each -B- component represent a substituted orunsibstituted ester comprising at least two acid ester functionalities.

In some embodiments, a method of making an elastomeric cross-linkedpolyester material comprising 1) providing a polyester materialcomprising a polymeric unit of the general formula (-A-B-)_(p), wherein:A-B has a chemical structure that is achieved when a polyol component A′is condensed with a polyacid component B′; and at least two A-B units inthe material each have at least one free hydroxyl or amino group, and 2)mixing the polyester material with a polyisocyanate so that anelastomeric cross-linked polyester material is produced.

BRIEF DESCRIPTION OF THE DRAWING

FIGS. 1A-1C shows macroscopic appearance of (FIG. 1A) representativePGSU-S films, (FIG. 1B) representative non-porous PGSU-SF films preparedthrough spin coat method, and (FIG. 1C) representative porous PGSU-SFfilms.

FIG. 2 demonstrates swelling properties of certain PGSU-S derivatives inPBS (37° C., 24hours) and ethanol (RT, 24 hours), and respective solcontent determined after ethanol extraction.

FIG. 3 shows in vitro degradations profile of certain PGSU-S discs (4 mmin diameter with an average thickness of 1 mm) and comparison withthermally cured PGS. Since enzymatic degradation may be the maindegradation mechanism of polyester-based polymers, these studies wereperformed in a cholesterol esterase solution (40 UN/mL) at 37° C. Thedegradation rate of PGSU-S derivative is observed to be considerablylower than thermally cured PGS and dependent on the urethane content.

FIGS. 4A-4C demonstrates in vitro biocompatibility of PGSU-S films.(FIG. 4A) Comparison of hMSC morphology when seeded in tissue culturepolystyrene (TCP) and PGSU-S 1:0.5 at day 1 and day 8. The scale bar is10 μm. (FIG. 4B) Percentage of adherent cells at 24 hours after cellseeding. (FIG. 4C) Proliferation kinetics for hMSC in PGS-U films andcomparison when seeded on TCP, measured using an MTT assay.

FIGS. 5A-5B shows swelling studies of PGSU-SF, and PGSU-SF with BSA orBSA-trehalose (1:1) encapsulated. (FIG. 5A) Macroscopic appearance offilms after 24 hours in PBS. (FIG. 5B) 24 hour swelling ratio aspercentage of sample dry weight. The co-encapsulation of BSA withtrehalose improves the water uptake of exemplary PGSU-SF films.

FIGS. 6A-6F shows chemical and mechanical characterization of exemplaryPGSU elastomers. (FIG. 6A) Synthetic scheme for PGSU. (FIG. 6B) Schemeson solvent-based (S) and solvent-free (SF) routes to synthesize PGSUmaterials. (FIG. 6C) FTIR analysis of PGS pre-polymer and PGSUelastomeric materials synthesized under solvent-based and solvent freeconditions. (FIG. 6D) Summary of mechanical properties and crosslinkingdegree of several PGSU derivatives. (FIG. 6E) Typical stress-strain ofPGSU-S films and thermally cured PGS elastomer and representative imagesof PGSU-S 1:0.5 films before and after tensile testing that revealminimal deformation. (FIG. 6F) Stress-strain profile of PGSU-SF 1:0.5films under cyclical tensile loads, the elastomer is able to maintainits tensile properties with minimal creep after 100 cycles.

FIGS. 7A-7F demonstrates in vivo subcutaneous and cardiacbiocompatibility and biodegradation of representative PGSU elastomers.(FIG. 7A) Representative images of H&E and anti-CD68 stainings of thesubcutaneous tissue surrounding PGSU-S elastomeric materials. Barsrepresent 200 μm. (FIG. 7B) Characterization of foreign body response toPGSU-S and PLGA implants through trough qualitative evaluation of theinflammatory infiltrate (classification: from 0 representing noinfiltrate and 4 severe infiltrate). (FIG. 7C) Subcutaneous in vivodegradation profile of PGSU-S films. (FIG. 7D) Morphologic evaluation ofPGSU-S cross-sections through SEM. Scale bars represent 50 μm. (FIG. 7E)Representative images of H&E sections of cardiac tissue in contact withPGSU-SF 1:0.3 elastomer for 1 and 4 weeks. (FIG. 7F) Cardiac functionbefore and 4 weeks after PGSU-SF implantation.

FIGS. 8A-8D illustrates sustained release of bioactive proteins fromPGSU-SF films. (FIG. 8A) Bioactivity of the lysozyme released fromPGSU-SF porous patches. (FIG. 8B) Selective encapsulation of rhodaminand FITC on intercalated PGSU layers using spin coating technique. Scalebars represent 20 μm. (FIG. 8C) Release kinetics of the model proteinBSA sieved to 75 and 32 μm particle size encapsulated on the internallayer of a trilayer spin-coated PGSU-SF 1:0.3 film. (FIG. 8D) Releasekinetics of the model protein BSA co-encapsulated with trehalose (1:1ratio) and sieved to 32 um particle size from internal and externalslayers of a trilayer spin-coated PGSU-SF 1:0.3 film.

DEFINITIONS

In order for the present disclosure to be more readily understood,certain terms are first defined below. Additional definitions for thefollowing terms and other terms are set forth throughout thespecification.

In this application, the use of “or” means “and/or” unless statedotherwise. As used in this application, the term “comprise” andvariations of the term, such as “comprising” and “comprises,” are notintended to exclude other additives, components, integers or steps. Asused in this application, the terms “about” and “approximately” are usedas equivalents. Any numerals used in this application with or withoutabout/approximately are meant to cover any normal fluctuationsappreciated by one of ordinary skill in the relevant art. In certainembodiments, the term “approximately” or “about” refers to a range ofvalues that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%,12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in eitherdirection (greater than or less than) of the stated reference valueunless otherwise stated or otherwise evident from the context (exceptwhere such number would exceed 100% of a possible value).

“Associated”: As used herein, the term “associated” typically refers totwo or more moieties connected with one another, either directly orindirectly (e.g., via one or more additional moieties that serve as alinking agent), to form a structure that is sufficiently stable so thatthe moieties remain connected under conditions in which the structure isused, e.g., physiological conditions. In some embodiments, associatedmoieties are attached to one another by one or more covalent bonds. Insome embodiments, associated moieties are attached to one another by amechanism that involves specific (but non-covalent) binding (e.g.streptavidin/avidin interactions, antibody/antigen interactions, etc.).Alternatively or additionally, a sufficient number of weakernon-covalent interactions can provide sufficient stability for moietiesto remain associated. Exemplary non-covalent interactions include, butare not limited to, affinity interactions, metal coordination, physicaladsorption, host-guest interactions, hydrophobic interactions, pistacking interactions, hydrogen bonding interactions, van der Waalsinteractions, magnetic interactions, electrostatic interactions,dipole-dipole interactions, etc.

“Biocompatible”: The term “biocompatible”, as used herein is intended todescribe materials that do not elicit a substantial detrimental responsein vivo. In certain embodiments, the materials are “biocompatible” ifthey are not toxic to cells. In certain embodiments, materials are“biocompatible” if their addition to cells in vitro results in less thanor equal to 20% cell death, and/or their administration in vivo does notinduce inflammation or other such adverse effects. In certainembodiments, materials are biodegradable.

“Biodegradable”: As used herein, “biodegradable” materials are thosethat, when introduced into cells, are broken down by cellular machinery(e.g., enzymatic degradation) or by hydrolysis into components thatcells can either reuse or dispose of without significant toxic effectson the cells. In certain embodiments, components generated by breakdownof a biodegradable material do not induce inflammation and/or otheradverse effects in vivo. In some embodiments, biodegradable materialsare enzymatically broken down. Alternatively or additionally, in someembodiments, biodegradable materials are broken down by hydrolysis. Insome embodiments, biodegradable polymeric materials break down intotheir component polymers. In some embodiments, breakdown ofbiodegradable materials (including, for example, biodegradable polymericmaterials) includes hydrolysis of ester bonds. In some embodiments,breakdown of materials (including, for example, biodegradable polymericmaterials) includes cleavage of urethane linkages.

“Hydrolytically degradable”: As used herein, “hydrolytically degradable”materials are those that degrade by hydrolytic cleavage. In someembodiments, hydrolytically degradable materials degrade in water. Insome embodiments, hydrolytically degradable materials degrade in waterin the absence of any other agents or materials. In some embodiments,hydrolytically degradable materials degrade completely by hydrolyticcleavage, e.g., in water. By contrast, the term “non-hydrolyticallydegradable” typically refers to materials that do not fully degrade byhydrolytic cleavage and/or in the presence of water (e.g., in the solepresence of water).

“Nucleic acid”: The term “nucleic acid” as used herein, refers to apolymer of nucleotides. In some embodiments, nucleic acids are orcontain deoxyribonucleic acids (DNA); in some embodiments, nucleic acidsare or contain ribonucleic acids (RNA). In some embodiments, nucleicacids include naturally-occurring nucleotides (e.g., adenosine,thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine,deoxyguanosine, and deoxycytidine). Alternatively or additionally, insome embodiments, nucleic acids include non-naturally-occurringnucleotides including, but not limited to, nucleoside analogs (e.g.,2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyladenosine, C5-propynylcytidine, C5-propynyluridine, C5-bromouridine,C5-fluorouridine, C5-iodouridine, C5-methylcytidine, 7-deazaadenosine,7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine,and 2-thiocytidine), chemically modified bases, biologically modifiedbases (e.g., methylated bases), intercalated bases, modified sugars(e.g., 2′-fluororibose, ribose, 2′-deoxyribose, arabinose, and hexose),or modified phosphate groups. In some embodiments, nucleic acids includephosphodiester backbone linkages; alternatively or additionally, in someembodiments, nucleic acids include one or more non-phosphodiesterbackbone linkages such as, for example, phosphorothioates and5′-N-phosphoramidite linkages. In some embodiments, a nucleic acid is anoligonucleotide in that it is relatively short (e.g., less that about5000, 4000, 3000, 2000, 1000, 900, 800, 700, 600, 500, 450, 400, 350,300, 250, 200, 150, 100, 90, 80, 70, 60, 50, 45, 40, 35, 30, 25, 20, 15,10 or fewer nucleotides in length).

“Physiological conditions”: The phrase “physiological conditions”, asused herein, relates to the range of chemical (e.g., pH, ionic strength)and biochemical (e.g., enzyme concentrations) conditions likely to beencountered in the intracellular and extracellular fluids of tissues.For most tissues, the physiological pH ranges from about 7.0 to 7.4.

“Polypeptide”: The term “polypeptide” as used herein, refers to a stringof at least three amino acids linked together by peptide bonds. In someembodiments, a polypeptide comprises naturally-occurring amino acids;alternatively or additionally, in some embodiments, a polypeptidecomprises one or more non-natural amino acids (i.e., compounds that donot occur in nature but that can be incorporated into a polypeptidechain; see, for example,http://www.cco.caltech.edu/^(˜)dadgrp/Unnatstruct.gif, which displaysstructures of non-natural amino acids that have been successfullyincorporated into functional ion channels) and/or amino acid analogs asare known in the art may alternatively be employed). In someembodiments, one or more of the amino acids in a protein may bemodified, for example, by the addition of a chemical entity such as acarbohydrate group, a phosphate group, a farnesyl group, an isofarnesylgroup, a fatty acid group, a linker for conjugation, functionalization,or other modification, etc.

“Polysaccharide”: The term “polysaccharide” refers to a polymer ofsugars. Typically, a polysaccharide comprises at least three sugars. Insome embodiments, a polypeptide comprises natural sugars (e.g., glucose,fructose, galactose, mannose, arabinose, ribose, and xylose);alternatively or additionally, in some embodiments, a polypeptidecomprises one or more non-natural amino acids (e.g, modified sugars suchas 2′-fluororibose, 2′-deoxyribose, and hexose).

“Small molecule”: As used herein, the term “small molecule” is used torefer to molecules, whether naturally-occurring or artificially created(e.g., via chemical synthesis), that have a relatively low molecularweight. Typically, small molecules are monomeric and have a molecularweight of less than about 1500 g/mol. Preferred small molecules arebiologically active in that they produce a local or systemic effect inanimals, preferably mammals, more preferably humans. In certainpreferred embodiments, the small molecule is a drug. Preferably, thoughnot necessarily, the drug is one that has already been deemed safe andeffective for use by the appropriate governmental agency or body. Forexample, drugs for human use listed by the FDA under 21 C.F.R. §§ 330.5,331 through 361, and 440 through 460; drugs for veterinary use listed bythe FDA under 21 C.F.R. §§ 500 through 589, incorporated herein byreference, are all considered acceptable for use in accordance with thepresent application.

“Substantial” or “substantive”: As used herein, the terms “substantial”or “substantive” and grammatic equivalents, refer to the qualitativecondition of exhibiting total or near-total extent or degree of acharacteristic or property of interest. One of ordinary skill in the artwill understand that biological and chemical phenomena rarely, if ever,go to completion and/or proceed to completeness or achieve or avoid anabsolute result.

“Transparent”: As used herein, the term “transparent” refers to a samplespecimen with a light transmission percentage of at least 75%, at least80%, at least 85%, at least 90%, at least 95%, or at least 99%. It ispossible to measure the degree of light transmission using ASTM D-1003(Standard Test Method for Haze and Luminous Transmittance of TransparentPlastics), and this test method is used to evaluate light transmissionand scattering of transparent plastics for a defined specimen thickness.In some embodiments, the term may refer to a sample specimen which has aconstant refractive index through the sample in the viewing direction.The perceived transparency or optical clarity is dependent on thethickness of the sample used for assessment, and the optical claritywill decrease with increasing thickness. Any areas of opaque material(such as colorants) or areas of different refractive index, will resultin a loss of optical clarity due to refraction and scattering. Opticalclarity is also dependent on surface reflections from the sample.

“Treating”: As used herein, the term refers to any method used topartially or completely alleviate, ameliorate, relieve, inhibit,prevent, delay onset of, reduce severity of and/or reduce incidence ofone or more symptoms or features of a particular disease, disorder,and/or condition. Treatment may be administered to a subject who doesnot exhibit signs of a disease and/or exhibits only early signs of thedisease for the purpose of decreasing the risk of developing pathologyassociated with the disease.

It will be appreciated that pre-polymer and polymer components such aspolyol and polycarboxylic acid, used to make inventive elastomericcompositions and materials, as described herein, may be substituted withany number of substituents or functional moieties. In general, the term“substituted” whether preceded by the term “optionally” or not, andsubstituents contained in formulas of this invention, refer to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. When more than one position in any givenstructure may be substituted with more than one substituent selectedfrom a specified group, the substituent may be either the same ordifferent at every position. As used herein, the term “substituted” iscontemplated to include all permissible substituents of organiccompounds. In a broad aspect, the permissible substituents includeacyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and nonaromatic substituents of organiccompounds. For purposes of this invention, heteroatoms such as nitrogenmay have hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valencies of theheteroatoms. Furthermore, this invention is not intended to be limitedin any manner by the permissible substituents of organic compounds.

In certain aspects, the term “substituted” is also contemplated toinclude substitution with a “biologically-active agent,” or substitutionwith another inventive elastomeric material, as defined herein.

The term “aliphatic,” as used herein, includes both saturated andunsaturated, nonaromatic, straight chain (i.e., unbranched), branched,acyclic, cyclic (i.e., carbocyclic), or polycyclic hydrocarbons, whichare optionally substituted with one or more functional groups. As willbe appreciated by one of ordinary skill in the art, “aliphatic” isintended herein to include, but is not limited to, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, asused herein, the term “alkyl” includes straight, branched and cyclicalkyl groups. An analogous convention applies to other generic termssuch as “alkenyl”, “alkynyl”, and the like. Furthermore, as used herein,the terms “alkyl”, “alkenyl”, “alkynyl”, and the like encompass bothsubstituted and unsubstituted groups. In certain embodiments, as usedherein, “aliphatic” is used to indicate those aliphatic groups (cyclic,acyclic, substituted, unsubstituted, branched or unbranched) having 1-20carbon atoms. Aliphatic group substituents include, but are not limitedto, any of the substituents described herein, that result in theformation of a stable moiety (for example, an aliphatic groupsubstituted with one or more aliphatic, alkyl, alkenyl, alkynyl,heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, sulfinyl,sulfonyl, oxo, imino, thiooxo, phosphino, cyano, amino, azido, nitro,hydroxy, thio, and/or halo groups).

The term “heteroaliphatic,” as used herein, refers to an aliphaticmoiety, as defined herein, that contain one or more oxygen, sulfur,nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms.In certain embodiments, heteroaliphatic moieties are substituted byindependent replacement of one or more of the hydrogen atoms thereonwith one or more substituents. Heteroaliphatic group substituentsinclude, but are not limited to, any of the substituents describedherein, that result in the formation of a stable moiety (for example, aheteroaliphatic group substituted with one or more aliphatic, alkyl,alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl,sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, amino, azido, nitro,hydroxy, thio, and/or halo groups).

The term “alkyl,” as used herein, refers to saturated, straight- orbranched-chain hydrocarbon radicals derived from a hydrocarbon moietycontaining between one and twenty carbon atoms by removal of a singlehydrogen atom. In some embodiments, the alkyl group employed in theinvention contains 1-20 carbon atoms. In another embodiment, the alkylgroup employed contains 1-12 carbon atoms. In still other embodiments,the alkyl group contains 1-6 carbon atoms. In yet another embodiments,the alkyl group contains 1-4 carbons. Examples of alkyl radicalsinclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pentyl, tert-butyl,n-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl,n-undecyl, dodecyl, and the like, which may bear one or moresubstituents. Alkyl group substituents include, but are not limited to,any of the substituents described herein, that result in the formationof a stable moiety (for example, an alkyl group substituted with one ormore aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl,sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, amino, azido, nitro,hydroxy, thio, and/or halo groups).

The term “alkenyl,” as used herein, denotes a monovalent group derivedfrom a straight- or branched-chain hydrocarbon moiety having at leastone carbon-carbon double bond by the removal of a single hydrogen atom.In certain embodiments, the alkenyl group employed in the inventioncontains 2-20 carbon atoms. In some embodiments, the alkenyl groupemployed in the invention contains 2-10 carbon atoms. In anotherembodiment, the alkenyl group employed contains 2-8 carbon atoms. Instill other embodiments, the alkenyl group contains 2-6 carbon atoms. Inyet another embodiments, the alkenyl group contains 2-4 carbons. Alkenylgroups include, for example, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, and the like, which may bear one or moresubstituents. Alkenyl group substituents include, but are not limitedto, any of the substituents described herein, that result in theformation of a stable moiety (for example, an alkenyl group substitutedwith one or more aliphatic, heteroaliphatic, heterocyclic, aryl,heteroaryl, acyl, sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, amino,azido, nitro, hydroxy, thio, and/or halo groups).

The term “alkynyl,” as used herein, refers to a monovalent group derivedfrom a straight- or branched-chain hydrocarbon having at least onecarbon-carbon triple bond by the removal of a single hydrogen atom. Incertain embodiments, the alkynyl group employed in the inventioncontains 2-20 carbon atoms. In some embodiments, the alkynyl groupemployed in the invention contains 2-10 carbon atoms. In anotherembodiment, the alkynyl group employed contains 2-8 carbon atoms. Instill other embodiments, the alkynyl group contains 2-6 carbon atoms. Instill other embodiments, the alkynyl group contains 2-4 carbon atoms.Representative alkynyl groups include, but are not limited to, ethynyl,2-propynyl (propargyl), 1-propynyl, and the like, which may bear one ormore substituents. Alkynyl group substituents include, but are notlimited to, any of the substituents described herein, that result in theformation of a stable moiety (for example, an alkynyl group substitutedwith one or more aliphatic, heteroaliphatic, heterocyclic, aryl,heteroaryl, acyl, sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, amino,azido, nitro, hydroxy, thio, and/or halo groups).

The term “alkylene,” as used herein, refers to a fully saturatedstraight- or branched-chain alkyl biradical containing between one andtwenty carbon atoms by removal of two hydrogen atoms (the term alkyl isdefined herein). In certain embodiments, an alkylene group issubstituted by independent replacement of one or more of the hydrogenatoms thereon with one or more substituents. Alkylene group substituentsinclude but are not limited to any of the substituents described hereinthat result in the formation of a stable moiety (such as, for example,an alkylene group substituted with one or more aliphatic,heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, sulfinyl,sulfonyl, cyano, amino, azido, nitro, hydroxyl, thiol, and/or halogroups).

The term “alkenylene,” as used herein, refers to a straight- orbranched-chain alkenyl biradical containing between two and twentycarbon atoms by removal of two hydrogen atoms (the term alkenyl isdefined herein). In certain embodiments, an alkenylene group issubstituted by independent replacement of one or more of the hydrogenatoms thereon with one or more substituents. Alkenylene groupsubstituents include but are not limited to any of the substituentsdescribed herein that result in the formation of a stable moiety (suchas, for example, an alkenylene group substituted with one or morealiphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl,sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, amino, azido, nitro,hydroxyl, thiol, and/or halo groups).

The term “alkynylene” as used herein, refers to a straight- orbranched-chain alkynyl biradical containing between two and twentycarbon atoms by removal of two hydrogen atoms (the term alkynyl isdefined herein). In certain embodiments, an alkynylene group issubstituted by independent replacement of one or more of the hydrogenatoms thereon with one or more substituents. Alkynylene groupsubstituents include but are not limited to any of the substituentsdescribed herein that result in the formation of a stable moiety (suchas, for example, an alkynylene group substituted with one or morealiphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl,sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, amino, azido, nitro,hydroxyl, thiol, and/or halo groups).

The term “heteroalkylene,” as used herein, refers to an alkylene group,as defined herein, that contains one or more oxygen, sulfur, nitrogen,phosphorus, or silicon atoms, e.g., in place of carbon atoms.

The term “heteroalkenylene,” as used herein, refers to an alkenylenegroup, as defined herein, that contains one or more oxygen, sulfur,nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms.

The term “heteroalkynylene,” as used herein, refers to an alkynylenegroup, as defined herein, that contains one or more oxygen, sulfur,nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms.

The term “heterocyclic,” or “heterocyclyl,” as used herein, refers to annon-aromatic, partially unsaturated or fully saturated, 3- to10-membered ring system, which includes single rings of 3 to 8 atoms insize, and bi- and tri-cyclic ring systems which may include aromaticfive- or six-membered aryl or heteroaryl groups fused to a non-aromaticring. These heterocyclic rings include those having from one to threeheteroatoms independently selected from oxygen, sulfur, and nitrogen, inwhich the nitrogen and sulfur heteroatoms may optionally be oxidized andthe nitrogen heteroatom may optionally be quaternized. In certainembodiments, the term heterocylic refers to a non-aromatic 5-, 6-, or7-membered ring or polycyclic group wherein at least one ring atom is aheteroatom selected from O, S, and N (wherein the nitrogen and sulfurheteroatoms may be optionally oxidized), and the remaining ring atomsare carbon, the radical being joined to the rest of the molecule via anyof the ring atoms. Heterocycyl groups include, but are not limited to, abi- or tri-cyclic group, comprising fused five, six, or seven-memberedrings having between one and three heteroatoms independently selectedfrom the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ringhas 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds,and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen andsulfur heteroatoms may be optionally oxidized, (iii) the nitrogenheteroatom may optionally be quaternized, and (iv) any of the aboveheterocyclic rings may be fused to an aryl or heteroaryl ring. Exemplaryheterocycles include azacyclopropanyl, azacyclobutanyl,1,3-diazatidinyl, piperidinyl, piperazinyl, azocanyl, thiaranyl,thietanyl, tetrahydrothiophenyl, dithiolanyl, thiacyclohexanyl,oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropuranyl, dioxanyl,oxathiolanyl, morpholinyl, thioxanyl, tetrahydronaphthyl, and the like,which may bear one or more substituents. Substituents include, but arenot limited to, any of the substituents described herein, that result inthe formation of a stable moiety (for example, a heterocyclic groupsubstituted with one or more aliphatic, heteroaliphatic, heterocyclic,aryl, heteroaryl, acyl, sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano,amino, azido, nitro, hydroxy, thio, and/or halo groups).

The term “aryl,” as used herein, refer to stable aromatic mono- orpolycyclic ring system having 3-20 ring atoms, of which all the ringatoms are carbon, and which may be substituted or unsubstituted. Incertain embodiments of the present invention, “aryl” refers to a mono,bi, or tricyclic C₄-C₂₀ aromatic ring system having one, two, or threearomatic rings which include, but not limited to, phenyl, biphenyl,naphthyl, and the like, which may bear one or more substituents. Arylsubstituents include, but are not limited to, any of the substituentsdescribed herein, that result in the formation of a stable moiety (forexample, an aryl group substituted with one or more aliphatic,heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, sulfinyl,sulfonyl, oxo, imino, thiooxo, cyano, amino, azido, nitro, hydroxy,thio, and/or halo groups).

The term “heteroaryl,” as used herein, refer to stable aromatic mono- orpolycyclic ring system having 3-20 ring atoms, of which one ring atom isselected from S, O, and N; zero, one, or two ring atoms are additionalheteroatoms independently selected from S, O, and N; and the remainingring atoms are carbon, the radical being joined to the rest of themolecule via any of the ring atoms. Exemplary heteroaryls include, butare not limited to pyrrolyl, pyrazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl,pyyrolizinyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl,indazolyl, quinolinyl, isoquinolinyl, quinolizinyl, cinnolinyl,quinazolynyl, phthalazinyl, naphthridinyl, quinoxalinyl, thiophenyl,thianaphthenyl, furanyl, benzofuranyl, benzothiazolyl, thiazolynyl,isothiazolyl, thiadiazolynyl, oxazolyl, isoxazolyl, oxadiaziolyl,oxadiaziolyl, and the like, which may bear one or more substituents.Heteroaryl substituents include, but are not limited to, any of thesubstituents described herein, that result in the formation of a stablemoiety (for example, a heteroaryl group substituted with one or morealiphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl,sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, amino, azido, nitro,hydroxy, thio, and/or halo groups).

The term “acyl,” as used herein, refers to a group having the generalformula—C(═O)R, where R is hydrogen, halogen, hydroxyl, thiol,optionally substituted amino, optionally substituted hydrazino,optionally substituted aliphatic, optionally substitutedheteroaliphatic, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,alkyloxy, alkylthioxy, alkylamino, dialkylamino, arylamino, diarylamino,optionally substituted aryl, optionally substituted heteroaryl, oroptionally substituted heterocycyl. Exemplary acyl groups includealdehydes (—CHO), carboxylic acids (—CO₂H), ketones (such as an acetylgroup [—(C═O)CH₃], esters, amides, carbonates, carbamates, and ureas.Acyl substituents include, but are not limited to, any of thesubstituents described herein, that result in the formation of a stablemoiety (for example, a heteroaryl group substituted with one or morealiphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl,heteroaryl, acyl, sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, amino,azido, nitro, hydroxy, thio, and/or halo groups).

The term “hydroxy,” or “hydroxyl,” as used herein, refers to a group ofthe formula (—OH). An “optionally substituted hydroxy” refers to a groupof the formula (—OR^(i) wherein R^(i) can be hydrogen, or anysubstituent which results in a stable moiety (for example, a hydroxygroup substituted with a suitable hydroxyl protecting group, analiphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl,heteroaryl, acyl, sulfinyl, and/or sulfonyl group).

The term “amino,” as used herein, refers to a group of the formula(—NH₂). An “optionally substituted amino” refers to a group of theformula (—NR^(h) ₂), wherein R^(h) can be hydrogen, or any substituent.Substituents include, but are not limited to, any of the substituentsdescribed herein, that result in the formation of a stable moiety (forexample, an amino group substituted with one or more aliphatic, alkyl,alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl,sulfinyl, sulfonyl, amino, nitro, hydroxy, and/or thio groups).

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

The present disclosure provides, among other things, elastomericmaterials, compositions, and methods of use and preparation. Providedmaterials are useful in a variety of medical and non-medicalapplications. For example, provided materials have many different usefulapplications, including in drug delivery (e.g., for the delivery oftherapeutic, diagnostic, or other agents) and in tissue engineering,(e.g., of tissue reconstruction, and medical patches).

In various embodiments, elastomeric cross-linked polyester materials areformed by the reaction of a multifunctional polyether or polyolcomponent A′ (i.e., a component comprising two or more OR groups, whereeach R is independently H and an alkyl) with a polyacid component B′(that is a component having a difunctional or higher order acid) to forma pre-polymer (-A-B-)_(p), wherein p is an integer greater than 1.Cross-linking of the pre-polymer generates elastomeric polyestermaterials. In some embodiments, cross-linking is performed byfunctionalization of hydroxyl group or amino groups on a pre-polymerbackbone or side chain with a polyisocyanates, to form an elastomericcross-linked polyester material that contains one or more urethanecrosslinks.

In some embodiments, an elastomeric cross-linked polyester materialcomprises a plurality of polymeric units of the general formula(-A-B-)_(p), wherein p is an integer greater than 1; and a plurality ofurethane cross-links each of which covalently links two A components toone another, which two linked A components each had at least one freehydroxyl group or amino groups prior to formation of the crosslink.

In some embodiments, a pre-polymer is a polyester material comprising apolymeric unit of the general formula (-A-B-)_(p) wherein p is aninteger greater than 1, and further wherein: A-B has a chemicalstructure that is achieved when a polyol component A′ is condensed witha polyacid component B′; and at least two A-B units in the material eachhas at least one free hydroxyl group or amine group.

In some embodiments, a pre-polymer is a polyester further comprising apolyamide backbone. For example, polyamine (that is a componentcomprising two or more amino groups) can be used to react with polyacidtogether with polyol or after reacting with polyol. Exemplary poly(esteramide) includes those described in Cheng, et al., Adv. Mater. 2011, 23,H95-H100, the contents of which are herein incorporated by reference.Without being bound to any particular theory, amides can form hydrogenbonds, which may affect the elasticity and/or mechanical properties ofmaterials.

Pre-Polymer

A pre-polymer used in accordance with the present disclosure may belinear or branched (i.e., non-linear). A pre-polymer, in someembodiments, is biodegradable and/or biocompatible.

In some embodiments, a pre-polymer is a polyester material comprising apolymeric unit of the general formula (-A-B-)_(p), wherein p is aninteger greater than 1. In some embodiments, A represents a substitutedor unsubstituted ester, wherein A comprises at least a hydroxyl group oramine group prior to crosslinking, while B represents a substituted orunsubstituted ester comprising at least two acid ester functionalities.

In some embodiments, a pre-polymer is a polyester material comprisingtwo or more different As or Bs. In some embodiments, each Aindependently represents a substituted or unsubstituted ester, whereineach A comprises at least a hydroxyl group or amine group prior tocrosslinking at least one free hydroxyl group or amino group; and/oreach B independently has represents a substituted or unsubstituted estercomprising at least two acid ester functionalities. For example, such apre-polymer can be formed by reacting one or more different polyolcomponents A′ (e.g., a first polyol with a free hydroxyl group and asecond polyol with a free amino group, at various ratios) with one ormore polyacid components B′.

In some embodiments, polyol-based polymers described in US PatentApplication Publication No. 2011-0008277, US Patent Publication No.7722894 and US Patent Publication No. 8143042, the contents of which arehereby incorporated by reference, are used as a pre-polymer to form anelastomeric cross-linked polyester material.

In certain embodiments, a pre-polymer can have the following formula:

wherein:

each instance of Z and L, are, independently, cyclic or acylic, branchedor unbranched, substituted or unsubstituted alkylene; cyclic or acylic,branched or unbranched, substituted or unsubstituted alkenylene; cyclicor acylic, branched or unbranched, substituted or unsubstitutedalkynylene; cyclic or acylic, branched or unbranched, substituted orunsubstituted heteroalkylene; cyclic or acylic, branched or unbranched,substituted or unsubstituted heteroalkenylene; cyclic or acylic,branched or unbranched, substituted or unsubstituted heteroalkynylene;substituted or unsubstituted arylene; substituted or unsubstitutedheteroarylene; or substituted or unsubstituted acylene;

each instance of R^(A) is, independently, hydrogen; Q; —OR^(C); acyl;cyclic or acylic, branched or unbranched, substituted or unsubstitutedalkyl; cyclic or acylic, branched or unbranched, substituted orunsubstituted alkenyl; cyclic or acylic, branched or unbranched,substituted or unsubstituted alkynyl; cyclic or acylic, branched orunbranched, substituted or unsubstituted heteroalkyl; cyclic or acylic,branched or unbranched, substituted or unsubstituted heteroalkenyl;cyclic or acylic, branched or unbranched, substituted or unsubstitutedheteroalkynyl; substituted or unsubstituted aryl; or substituted orunsubstituted heteroaryl; or two R^(A) groups are joined to form (═O),(═S), or (═NR^(B)), wherein R^(B) is hydrogen; a suitable aminoprotecting group; substituted or unsubstituted amino; acyl; cyclic oracylic, branched or unbranched, substituted or unsubstituted alkyl;cyclic or acylic, branched or unbranched, substituted or unsubstitutedalkenyl; cyclic or acylic, branched or unbranched, substituted orunsubstituted alkynyl; cyclic or acylic, branched or unbranched,substituted or unsubstituted heteroalkyl; cyclic or acylic, branched orunbranched, substituted or unsubstituted heteroalkenyl; cyclic oracylic, branched or unbranched, substituted or unsubstitutedheteroalkynyl; substituted or unsubstituted aryl; or substituted orunsubstituted heteroaryl;

W is hydrogen, or a suitable carboxylic acid protecting group;

Q is —OR^(C), wherein R^(C) is hydrogen, acyl; cyclic or acylic,branched or unbranched, substituted or unsubstituted alkyl; cyclic oracylic, branched or unbranched, substituted or unsubstituted alkenyl;cyclic or acylic, branched or unbranched, substituted or unsubstitutedalkynyl; cyclic or acylic, branched or unbranched, substituted orunsubstituted heteroalkyl; cyclic or acylic, branched or unbranched,substituted or unsubstituted heteroalkenyl; cyclic or acylic, branchedor unbranched, substituted or unsubstituted heteroalkynyl; substitutedor unsubstituted aryl; or substituted or unsubstituted heteroaryl;

and R^(A) and/or L comprises at least a free hydroxyl/amino group priorto crosslinking.

In certain embodiments, R^(A) is hydrogen.

In certain embodiments, L is hydroxyl-substituted methylene (i.e.,—CH(OH)—).

In certain embodiments, j is 0 to 6. In certain embodiments, k is 0 to6.

In certain embodiments, m is 1 to 100. In certain embodiments, m is 1 to50. In certain embodiments, m is 1 to 25. In certain embodiments, m is 1to 10. In certain embodiments, m is 1 to 5. In certain embodiments, m is1 to 4. In certain embodiments, m is 1 to 3. In certain embodiments, mis 1 to 2. In certain embodiments, m is 1.

In certain embodiments, n is 1 to 100. In certain embodiments, n is 1 to50. In certain embodiments, n is 1 to 25. In certain embodiments, n is 1to 10. In certain embodiments, n is 1 to 5. In certain embodiments, n is1 to 4. In certain embodiments, n is 1 to 3. In certain embodiments, nis 1 to 2. In certain embodiments, n is 1.

In certain embodiments, p is 1 to 900. In certain embodiments, p is 1 to800. In certain embodiments, p is 1 to 700. In certain embodiments, p is1 to 600. In certain embodiments, p is 1 to 500. In certain embodiments,p is 1 to 400. In certain embodiments, p is 1 to 300. In certainembodiments, p is 1 to 200. In certain embodiments, p is 1 to 100. Incertain embodiments, p is 1 to 50. In certain embodiments, p is 1 to 25.In certain embodiments, p is 1 to 10. In certain embodiments, p is 1 to5. In accordance with the present disclosure, p varies depending on therepeat unit of A and B, in some embodiments, to achieve a suitablemolecular weight of a pre-polymer.

In some embodiments, a pre-polymer has a molecular weight greater thanabout 3000 Da, about 4000 Da, about 5000 Da, about 6000 Da, about 7000Da, about 8000 Da, about 9000 Da, about 10000 Da, about 11000 Da, about12000 Da, about 13000 Da, about 14000 Da, about 15000 Da, about 16000Da, about 17000 Da, about 18000 Da, about 19000 Da, about 20000 Da,about 25000 Da, or about 50000 Da. In some embodiments, a pre-polymerhas a molecular weight less than about 4000 Da, about 5000 Da, about6000 Da, about 7000 Da, about 8000 Da, about 9000 Da, about 10000 Da,about 11000 Da, about 12000 Da, about 13000 Da, about 14000 Da, about15000 Da, about 16000 Da, about 17000 Da, about 18000 Da, about 19000Da, about 20000 Da, about 25000 Da, about 50000 Da, or about 100000 Da.In some embodiments, a pre-polymer has a molecular weight ranging fromabout 3000 Da to 50000 Da, from about 5000 Da to 30000 Da, or of any twovalues above.

In some embodiments, a pre-polymer for use in accordance with thepresent invention has a molecular weight within a range between a lowerboundary and an upper boundary. In some embodiments, the lower boundaryis selected from the group consisting of about 3000 Da, about 4000 Da,about 5000 Da, about 6000 Da, about 7000 Da, about 8000 Da, about 9000Da, about 10000 Da, about 11000 Da, about 12000 Da, about 13000 Da,about 14000 Da, about 15000 Da, about 16000 Da, about 17000 Da, about18000 Da, about 19000 Da, about 20000 Da, about 25000 Da, and about50000 Da; in some embodiments, the upper boundary is selected from thegroup consisting of about 4000 Da, about 5000 Da, about 6000 Da, about7000 Da, about 8000 Da, about 9000 Da, about 10000 Da, about 11000 Da,about 12000 Da, about 13000 Da, about 14000 Da, about 15000 Da, about16000 Da, about 17000 Da, about 18000 Da, about 19000 Da, about 20000Da, about 25000 Da, about 50000 Da, and about 100000 Da. Without beingbound to any particular theory, a molecular weight of a pre-polymer canaffect the crosslinking rate and density.

As illustrated in the Examples provided herein, the present inventiondemonstrates, among other things, that certain elastomeric materials asdescribed herein with surprisingly good and/or useful properties aregenerated through use of a pre-polymer whose molecular weight is withinthe range of 5000 Da to 20000 Da or 9000 Da to 15000 Da.

In some embodiments, a pre-polymer described herein can be formed when apolyol component A′ is condensed with a polyacid component B′; and atleast two A-B units that is achieved each has at least one free hydroxylor amino group.

In some embodiments, a wide variety of a polyol component A′, can beused in the production of elastomeric compositions and materialsaccording to various embodiments of the present disclosure. In certainembodiments, a polyol component A′ is selected from Table 1 (providedbelow). In certain embodiments, a polyol component A′ is selected fromglycerol, erythritol, threitol, ribitol, arabinitol, xylitol, allitol,altritol, galactritol, sorbitol, mannitol, iditol, lactitol, isomalt, ormaltitol, wherein the functional groups present on the polyol areoptionally substituted, as described above. In certain embodiments, apolyol component A′ is selected from xylitol, mannitol, sorbitol, ormaltitol, wherein the functional groups present on the polyol areoptionally substituted, as described above.

TABLE 1 Exemplary polyols Sugar alcohols

Cyclic sugars e.g., maltitol Maltitol, lactitol, isomalt

e.g., lactitol

e.g., isomalt

e.g., monosaccharides which include hexoses (allose, altrose, glucose,mannose, gulose, idose, galactose, talose) and pentoses (ribose,arabinaose, xylose, lyxose); disaccharides which include maltose,cellobiose, sucrose, and lactose; polysaccharides which include amylose,amylopectin, glycogen, and cellulose; fructofuranose, glucopyranose,sorbose, rhaminose, tagatose, apiose, deoxyribose, ribofructose,1,3,6-tri-O-galloyl-β-D-glucopyranose (tannic acid); amino-containingcyclic sugars (e.g., N-acetyl glucoseamine (sialic acid), glucoseamine);amide-containing cyclic sugars (e.g., glucoronamide); carboxylcontaining sugars (e.g., galacturonic acid); as well as protectedderivatives, such as alkyl- and acyl- derivatives, and stereoisomersthereof. Pentaerythritols, and structural derivatives thereof, such asmethylated, ethylated, acetate, ethoxylate, and propoxylate derivatives.e.g.,  

Phenolic polyols e.g., resorcinol, orcinol, 2-methylresorcinol,phloroglucinol, 1,2,4 benzenetriol, pyrogallol, 4-ethylresorcinol,5-methyl benzene1,2,3triol, 2-methoxyhydroquinone, 3,5dihydroxylbenzylalcohol, 2,4,6 trihydroxytoluene, 2,4,5-trihydroxybenzaldehyde,2,3,4-trihydroxybenzaldehyde, 2,4,6,-trihydroxybenzaldehyde,gallacetophenone, 3,4,5-trihydroxybenzamide, gallic acid, 2,4,5-trihydroxybenzoic acid, 2,3,4- trihydroxybenzoic acid, 2-nitrophloroglucinol; naturally occurring phenolic compounds, such ascarnosol, rosmanol (7α-), epirosmanol (7β-) from rosemary (Rosmarinusofficialis L.); rosemaric acid from rosemary and oregano (Oreganumvulgare L.); capsicin and dihydrocapsicin, hot-tasting compounds, fromhot pepper (Capsicinum annuum L.); ferulic acid amide of tyramine fromblack pepper (Piper nigrum L.); piperin-related compound from thyme(Thymus serpyllum L.); and apigenin and apiin from parsley Miscellaneouspolyols e.g.,

In some embodiments, any of a wide variety of a polyacid component B′,can be used in the production of elastomeric compositions and materialsaccording to various embodiments of the present disclosure, including,but are not limited to, glutaric acid (5 carbons), adipic acid (6carbons), pimelic acid (7 carbons), suberic acid (8 carbons), andazelaic acid (nine carbons). Exemplary long chain diacids includediacids having more than 10, more than 15, more than 20, and more than25 carbon atoms. Non-aliphatic diacids can be used. For example,versions of the above diacids having one or more double bonds can beemployed to produce glycerol-diacid co-polymers. Amines and aromaticgroups can be incorporated into the carbon chain. Exemplary aromaticdiacids include terephthalic acid and carboxyphenoxypropane. The diacidscan also include substituents as well. For example, in variousembodiments, reactive groups like amino and hydroxyl can be usedincrease the number of sites available for cross-linking. In variousembodiments, amino acids and other biomolecules can be used to modifythe biological properties of elastomeric materials. In variousembodiments, aromatic groups, aliphatic groups, and halogen atoms can beused to modify the inter-chain interactions within elastomericmaterials.

In certain embodiments, a polyacid component B′ is selected from Table 2(provided below). In certain embodiments, a polyacid component B′ isselected from the group consisting of succinic acid, fumaric acid,α-ketoglutaric acid, oxaloacetic acid, malic acid, oxalosuccinic acid,isocitric acid, cis-aconitic acid, citric acid, 2-hydroxy-malonic acid,tartaric acid, ribaric acid, arabanaric acid, xylaric acid, allaricacid, altraric acid, galacteric acid, glucaric acid, or mannaric acid,dimercaptosuccinic acid, oxalic acid, malonic acid, succinic acid,glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid,and sebacic acid, wherein the functional groups present onpolycarboxylic acids are optionally substituted, as described above. Incertain embodiments, a polyacid component B′ is citric acid. In certainembodiments, a polyacid component B′ is sebacic acid. In certainembodiments a polyacid component B′ is a polycarboxylic acid selectedfrom glutaric acid, citric acid and sebacic acid, wherein the functionalgroups present on polycarboxylic acids are optionally substituted, asdescribed herein.

TABLE 2 Exemplary Polycarboxylic Acids Oxalic acid

Malonic acid (propanedioic acid)

Succinic acid, succinate (butanedioic acid)

Glutaric acid (pentanedioic acid)

Adipic acid (hexanedioic acid)

Pimelic acid (heptanedioic acid)

Suberic acid (octanedioic acid)

Azelaic acid (nonanedioic acid)

Sebacic acid (decanedioic acid)

Aldaric acids

Aspartic acid

DMSA (Dimercapto- succinic acid, 2,3-bis- sulfanylbutanedioic acid)

fumaric acid

maleic acid

glutaconic acid

glutamic Acid, Gln, Glutamate

α-ketoglutaric acid; Oxopentanedioic acid;

β-ketoglutaric acid

Oxaloacetic acid; Oxaloacetate;

Malic acid; Malate; hydroxysuccinic acid

fumaric acid; fumarate

oxalosuccinic acid; oxalosuccinate

isocitric acid; isocitrate

cis-aconitic acid

Citric acid; citrate

Itaconic acid; methylenesuccinic acid

mesaconic acid; (2E)-2-Methyl-2- butenedioic acid

Tartaric acid, 2,3- dihydroxybutanedioic acid, 3- dihydroxysuccinic

acid; threaric acid; uvic acid; paratartaric acid   

Traumatic acid; dodec-2-enedioic acid

Urethane Crosslinking

Cross-linking can be performed by functionalization of hydroxyl group oramino groups on a pre-polymer backbone or side chain with apolyisocyanate (that is a component having a difunctional or higherorder isocyanate), to form an elastomeric cross-linked polyestermaterial that contains one or more urethane crosslinks. In someembodiments, in addition to chemical interchain crosslinks (e.g.,urethane linkages), physical interchain crosslinks are formed in anelastomeric cross-linked polyester material. Exemplary physicalcrosslinks are based on hydrogen bonding interactions, affinityinteractions, metal coordination, physical adsorption, host-guestinteractions, hydrophobic interactions, pi stacking interactions, vander Waals interactions, magnetic interactions, electrostaticinteractions, and dipole-dipole interactions.

Various polyisocyanates can be used for crosslinking in accordance withthe present disclosure. In some embodiments, polyisocyanates for use inthe present invention include aliphatic polyisocyanates. Exemplaryaliphatic polyisocyanates include, but are not limited to, lysinediisocyanate, an alkyl ester of lysine diisocyanate (for example, themethyl ester or the ethyl ester), lysine triisocyanate, hexamethylenediisocyanate, isophorone diisocyanate (IPDI), 4,4′-dicyclohexylmethanediisocyanate (H₁₂MDI), cyclohexyl diisocyanate,2,2,4-(2,2,4)-trimethylhexamethylene diisocyanate (TMDI), dimersprepared form aliphatic polyisocyanates, trimers prepared from aliphaticpolyisocyanates and/or mixtures thereof. In some embodiments,hexamethylene diisocyanate (HDI) trimer sold as Desmodur N3300A can be apolyisocyanate utilized in the present invention.

Methods

The present inventions among other things provide methods of formingbiodegradable elastomeric compositions and materials. In someembodiments, elastomeric compositions and materials are used to formstructures (e.g., scaffold) and/or to coat devices.

To make a pre-polymer, various molar ratios of polyol to polyacid can beused in accordance with the present disclosure. In some embodiments,such a molar ratio is more or less than about 1:0.1, about 1:0.2, about1:0.3, about 1:0.4, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8,about 1:0.9, about 1:1, about 1:1.1, about 1:1.2, about 1:1.3, about1:1.4, about 1:1.5, about 1:1.6, about 1:1.7 about 1:1.8 about 1:1.9,about 1:2 or about 1:2.5. In some embodiments, such a ratio is in arange of 1:0.5 to 1:2, or between any two values above.

As appreciated by a person of ordinary skill in the art, a molar ratioof a free reactive group (e.g., a hydroxyl or amino group) of apre-polymer to a polyisocyanate or a reactive isocyanate group of apolyisocyanate dictates the crosslinking rate and density. Such a molarratio can vary to adjust properties of an elastomeric cross-linkedpolyester material formed after crosslinking. In some embodiments, sucha ratio is more or less than about 1:0.1, about 1:0.2, about 1:0.3,about 1:0.4, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about1:0.9, about 1:1, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4,about 1:1.5, about 1:1.6, about 1:1.7 about 1:1.8 about 1:1.9, about 1:2or about 1:2.5. In some embodiments, such a molar ratio is in a range of1:0.3 to 1:1, 1:0.5 to 1:0.8 or between any two values above.

As illustrated in the Examples provided herein, the present inventiondemonstrates, among other things, that certain elastomeric materials asdescribed herein can be prepared at low temperature rapidly bycrosslinking a pre-polymer with polyisocyanate. The temperature at whichthe production of a pre-polymer is performed can be higher than that forcrosslinking. In some embodiments, crosslinking a pre-polymer withpolyisocyanate in accordance with the present disclosure is conducted ata temperature less than about 100° C., about 90° C., about 80° C., about70° C., about 60° C., about 55° C., about 50° C., about 45° C., about40° C., about 35° C., about 30° C., about 35° C., about 30° C., about25° C., or even about 20° C.

In some embodiments, production of a pre-polymer and crosslinking aredone in one step. Alternatively, production of a pre-polymer is followedby crosslinking in a two-step process.

In some embodiments, production of a pre-polymer is followed bycrosslinking in the presence of at least one solvent. In someembodiments, production of a pre-polymer is followed by crosslinkingsurprisingly in a solvent free condition. In certain embodiments, asolvent-free crosslinking is conducted at a room temperature. In certainembodiments, a solvent-free crosslinking is conducted at a bodytemperature, which is particularly useful for in situ crosslinking of apre-polymer.

In some embodiments, at least one catalyst is used for crosslinking withpolyisocyanate. A catalyst, for example, can be non-toxic (in aconcentration that may remain in elastomeric compositions andmaterials).

In some embodiments, a catalyst is an organometallic compound. In someembodiments, catalyst is a tertiary amine compound. Exemplary catalystsincludes, but are not limited to, stannous octoate (an organobismuthcompound), triethylene diamine, bis(dimethylaminoethyl)ether,dimethylethanolamine, dibutyltin dilaurate, and Coscat organometalliccatalysts manufactured by Vertullus (a bismuth based catalyst), or anycombination thereof.

A porogen may be used to generate porous elastomeric compositions andmaterials. In some embodiments, a porogen reserves space in anelastomeric composition or material in the process of formation and thenthe porogen diffuses, dissolves, or degrades, thereby inducing porosityinto the formed elastomeric composition or material. In this wayporogens provide latent pores. In some embodiments, a porogen is leachedout of an elastomeric composition or material before use.

A porogen may be a gas (e.g., carbon dioxide, nitrogen, or other inertgas), liquid (e.g., water, biological fluid), or solid. In someembodiments, porogens are water soluble such as salts, sugars (e.g.,sugar alcohols), polysaccharides (e.g., dextran (poly(dextrose)), watersoluble small molecules, etc. Additionally or alternatively, porogenscan be natural or synthetic polymers, oligomers, or monomers that arewater soluble or degrade quickly under physiological conditions.Exemplary polymeric porogens include polyethylene glycol,poly(vinylpyrollidone), pullulan, poly(glycolide), poly(lactide),poly(lactide-co-glycolide), other polyesters, and starches.

Material Properties

In various embodiments, an elastomeric cross-linked polyester materialformed from the a composition of the present invention, has one or moreof characteristics including Young's modulus, tensile strength,elongation, size deformation, transparency to light, etc.

In some embodiments, an elastomeric material has Young's modulus more orless than about 0.2 MPa, about 0.5 MPa, about 1 MPa, about 2 MPa, about5 MPa, about 8 MPa, about 10 MPa, about 12 MPa, about 15 MPa, about 18MPa, about 20 MPa, about 22 MPa, about 25 MPa, about 28 MPa, about 30MPa, about 40 MPa or even 50 MPa. In some embodiments, an elastomericmaterial has Young's modulus in a range of 0.5 MPa and 25 MPa, 1 MPa and20 MPa, 5 MPa and 15 MPa, or any two values above.

In some embodiments, an elastomeric material has a tensile strength moreor less than about 0.2 MPa, about 0.5 MPa, about 1 MPa, about 2 MPa,about 5 MPa, about 8 MPa, about 10 MPa, about 12 MPa, about 15 MPa,about 18 MPa, about 20 MPa, about 22 MPa, about 25 MPa, about 28 MPa,about 30 MPa, about 40 MPa or even 50 MPa. In some embodiments, anelastomeric material has a tensile strength in a range of about 0.5 MPaand about 15 MPa, about 1 MPa and about 10 MPa, or any two values above.

In some embodiments, an elastomeric material has an elongation more orless than about 10%, about 20%, about 50%, about 80%, about 100%, about150%, about 200%, about 300%, about 400%, about 500%, about 600%, about700%, or about 800%. In some embodiments, an elastomeric material has anelongation in a range of about 50% and about 600%, about 200% and about500%, or any two values above.

In some embodiments, an elastomeric material has size deformation belowthan about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, oreven about 50% of its initial length, after tensile loading.

In some embodiments, an elastomeric material has a tensile strengthstable within about 1%, about 2%, about 3%, about 5%, about 10%, about15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%,or about 50% of the initial sample strength over 100 cycles ofextension.

In some embodiments, an elastomeric material has size deformation stablewithin about 1%, about 2%, about 3%, about 5%, about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, orabout 50% of the initial sample length over 100 cycles of extension.

In some embodiments, an elastomeric material is substantiallytransparent to light before and/or after exposure to water. For example,the transparency can be tested when an elastomeric material is made intoa non-porous film form with a thickness of 200 μm. In certainembodiments, an elastomeric material in a non-porous film form with athickness of 200 um has a light transmission percentage more than about75%, about 80%, about 85%, about 90%, about 95%, or about 99%.

As illustrated in the Examples provided herein, the present inventiondemonstrates, among other things, that certain elastomeric materials asdescribed herein with surprisingly transparency to light after exposureto water.

Agents for Delivery

Elastomeric compositions and materials in accordance with the presentinvention can comprise one or more agents for delivery. In someembodiments, one or more agents are associated independently with anelastomeric material.

In some embodiments, an agent for delivery associated with anelastomeric material is released when the elastomeric material degrades.Additionally or alternatively, an agent is release by diffusion.

In theory, any agents including, for example, therapeutic agents (e.g.antibiotics, NSAIDs, glaucoma medications, angiogenesis inhibitors,neuroprotective agents), cytotoxic agents, diagnostic agents (e.g.contrast agents; radionuclides; and fluorescent, luminescent, andmagnetic moieties), prophylactic agents (e.g. vaccines), and/ornutraceutical agents (e.g. vitamins, minerals, etc.) may be associatedwith an elastomeric material disclosed herein to be released.

In some embodiments, agents for delivery utilized in accordance with thepresent disclosure are one or more therapeutic agents. Exemplary agentsinclude, but are not limited to, small molecules (e.g. cytotoxicagents), nucleic acids (e.g., siRNA, RNAi, and microRNA agents),proteins (e.g. antibodies), peptides, lipids, carbohydrates, hormones,metals, radioactive elements and compounds, drugs, vaccines,immunological agents, etc., and/or combinations thereof. In someembodiments, a therapeutic agent to be delivered is an agent useful incombating inflammation and/or infection.

In some embodiments, a therapeutic agent is a small molecule and/ororganic compound with pharmaceutical activity. In some embodiments, atherapeutic agent is a clinically-used drug. In some embodiments, atherapeutic agent is or comprises an antibiotic, anti-viral agent,anesthetic, anticoagulant, anti-cancer agent, inhibitor of an enzyme,steroidal agent, anti-inflammatory agent, anti-neoplastic agent,antigen, vaccine, antibody, decongestant, antihypertensive, sedative,birth control agent, progestational agent, anti-cholinergic, analgesic,anti-depressant, anti-psychotic, β-adrenergic blocking agent, diuretic,cardiovascular active agent, vasoactive agent, anti-glaucoma agent,neuroprotectant, angiogenesis inhibitor, etc.

In some embodiments, a therapeutic agent may be a mixture ofpharmaceutically active agents. For example, a local anesthetic may bedelivered in combination with an anti-inflammatory agent such as asteroid. Local anesthetics may also be administered with vasoactiveagents such as epinephrine. To give but another example, an antibioticmay be combined with an inhibitor of the enzyme commonly produced bybacteria to inactivate the antibiotic (e.g., penicillin and clavulanicacid).

In some embodiments, a therapeutic agent may be an antibiotic. Exemplaryantibiotics include, but are not limited to, β-lactam antibiotics,macrolides, monobactams, rifamycins, tetracyclines, chloramphenicol,clindamycin, lincomycin, fusidic acid, novobiocin, fosfomycin, fusidatesodium, capreomycin, colistimethate, gramicidin, minocycline,doxycycline, bacitracin, erythromycin, nalidixic acid, vancomycin, andtrimethoprim. For example, β-lactam antibiotics can be ampicillin,aziocillin, aztreonam, carbenicillin, cefoperazone, ceftriaxone,cephaloridine, cephalothin, cloxacillin, moxalactam, penicillin G,piperacillin, ticarcillin and any combination thereof.

An antibiotic used in accordance with the present disclosure may bebacteriocidial or bacteriostatic. Other anti-microbial agents may alsobe used in accordance with the present disclosure. For example,anti-viral agents, anti-protazoal agents, anti-parasitic agents, etc.may be of use.

In some embodiments, a therapeutic agent may be an anti-inflammatoryagent. Anti-inflammatory agents may include corticosteroids (e.g.,glucocorticoids), cycloplegics, non-steroidal anti-inflammatory drusg(NSAIDs), immune selective anti-inflammatory derivatives (ImSAIDs), andany combination thereof. Exemplary NSAIDs include, but not limited to,celecoxib (Celebrex®); rofecoxib (Vioxx®), etoricoxib (Arcoxia®),meloxicam (Mobic®), valdecoxib, diclofenac (Voltaren®, Cataflam®),etodolac (Lodine®), sulindac (Clinori®), aspirin, alclofenac,fenclofenac, diflunisal (Dolobid®), benorylate, fosfosal, salicylic acidincluding acetylsalicylic acid, sodium acetylsalicylic acid, calciumacetylsalicylic acid, and sodium salicylate; ibuprofen (Motrin),ketoprofen, carprofen, fenbufen, flurbiprofen, oxaprozin, suprofen,triaprofenic acid, fenoprofen, indoprofen, piroprofen, flufenamic,mefenamic, meclofenamic, niflumic, salsalate, rolmerin, fentiazac,tilomisole, oxyphenbutazone, phenylbutazone, apazone, feprazone,sudoxicam, isoxicam, tenoxicam, piroxicam (Feldene®), indomethacin(Indocin®), nabumetone (Relafen®), naproxen (Naprosyn®), tolmetin,lumiracoxib, parecoxib, licofelone (ML3000), including pharmaceuticallyacceptable salts, isomers, enantiomers, derivatives, prodrugs, crystalpolymorphs, amorphous modifications, co-crystals and combinationsthereof.

Additionally or alternatively, an agent having NSAID-like activity canbe used. Suitable compounds having NSAID activity include, but arenon-limited to, the non-selective COX inhibitors, selective COX-2inhibitors, selective COX-1 inhibitors, and COX-LOX inhibitors, as wellas pharmaceutically acceptable salts, isomers, enantiomers, polymorphiccrystal forms including the amorphous form, co-crystals, derivatives,prodrugs thereof.

Those skilled in the art will recognize that this is an exemplary, notcomprehensive, list of agents that can be released using compositionsand methods in accordance with the present disclosure. In addition to atherapeutic agent or alternatively, various other agents may beassociated with elastomeric compositions and materials in accordancewith the present disclosure.

Uses and Applications

In various embodiments, the present inventions provide biodegradableelastomeric compositions and materials tunable for use in many medicalor non-medical applications. Exemplary applications described in USPatent Publication No. 7722894 and US Patent Publication No. 8143042 canbe applicable in accordance with the present disclsoure, the contents ofboth references are hereby incorporated by reference.

Fabrication of provided biodegradable elastomeric compositions andmaterials can be done prior to use. Additionally or alternatively, atleast partial fabrication can be done in situ. For example, a precursorcomposition comprising a pre-polymer and a crosslink can be implantedand cured in vivo. In some embodiments, a precursor composition isinjected. In some embodiments, a precursor composition is implanted orapplied during surgery.

In some embodiments, elastomeric materials, in particular, those aretransparent can be used in a form of contact lenses and/or patches onthe surface of an eye. Such contact lenses can comprises ocular drugsfor delivery. In some embodiments, transparent elastomeric materials canbe part of a device transplanted into an eye to treat maculardegeneration, diabetic retinopathy, glaucoma and/other eye diseases. Forexample, they can be part of a punctal plug.

In some embodiments, elastomeric materials, in particular, those aretransparent can be used in a form of medical patches. Such patches canbe attached to tissue using light activated adhesives (non-transparentmaterials cannot). If the procedure is done minimally invasive, it maybe beneficial that a patch maintains its optically transparentproperties after contact with body fluids. Such patches can be helpfulfor observation of underlying tissue after defect closure. For example,if a patch is used to close a stomach ulcer, an endoscopy can be done tosee if the ulcer is closing properly.

Due to its elastomeric nature, the compositions and materials of thepresent inventions can be used in tissue engineering/reconstruction oftissues, especially muscle tissue, bladder, artery and heart valves.Additional or alternatively, elastomeric compositions and materials canbe applied to other tissues such as lung, colon, tendon, ligament, dura,brain, etc. In certain embodiments, elastomeric compositions andmaterials are used as a bandage for skin or on other tissues.

For example, in various embodiments, an elastomeric composition ormaterial of the present invention can be used in the form of tubes,e.g., for peripheral nerve reconstruction. Preferably, the tube isconstructed to withstand pressure of the surrounding tissue and guidethe nerve in its outgrowth, substantially unhampered by scar tissueformation. In peripheral nerve regeneration applications, it ispreferred that the material be functionalized (e.g., with GRGD) tofacilitate the attachment and guidance of Schwann cells.

For example, in various embodiments, a biodegradable elastomeric of thepresent invention can be used as a matrix, scaffold, or structure forcell attachment and/or encapsulation. In some embodiments,short-peptides (e.g., GRGD) can be incorporated into a biodegradableelastomeric material of the present invention to enhance cell adhesion.Incorporation of these short peptides can be achieved by mixing thefunctionalized peptides with a pre-polymer followed by crosslinking. Forexample, a GRGD peptide can be functionalized with a poly(ethyleneglycol) spacers and a hydroxyl or amino group.

In various embodiments, the present inventions provide biodegradableelastomeric compositions and materials as a 3D matrix for encapsulationand proliferation of cells. For example, matrixes may be seeded with avariety of cells, such as, tenocytes, fibroblasts, ligament cells,endothelial cells, epithelial cells, muscle cells, nerve cells, kidneycells, bladder cells, intestinal cells, chondrocytes, bone-formingcells, stem cells such as human embryonic stem cells or mesenchymal stemcells, and others. In certain embodiments, matrixes are configured forstem cells.

Other medical applications may also benefit from elastomericcompositions and materials of the present invention. For example, afterabdominal surgery, the intestines and other abdominal organs tend toadhere to one another and to the abdominal wall. It is thought that thisadhesion results from post-surgical inflammation, however,anti-inflammatory drugs delivered directly to the abdominal regiondissipate quickly. Elastomeric compositions and materials may be used todeliver anti-inflammatory drugs to the abdominal region. It may beimplanted between the abdominal wall and internal organs, for example,by attaching it to the abdominal wall, without cutting internal organs,which would lead to infection. The anti-inflammatory drug can bereleased from elastomeric compositions and materials over a period ofmonths. While previous researchers have attempted to use hydrogels,hyaluronic acid-based membranes, and other materials to solve theseproblems, such materials tend to degrade quickly in the body; a longerresident period is necessary to prevent adhesion.

Elastomeric compositions and materials may be used to coat any medicaldevices. In some embodiments, a medical device is an implantable device.

In some embodiments, an elastomeric composition or material can be usedto coat a metallic stent. It may expand with the stent without ripping,while the stiffness of the metal stent will prevent the elastomericcomposition or material from elastically assuming its previous shape. Anelastomeric composition or material may release heparin or otheranti-coagulants or anti-inflammatory agents to prevent the formation ofclots or scar tissue, which could close off the blood vessel or throwoff a thrombus that could cause circulatory problems, including stroke,elsewhere in the body. Alternatively or in addition, angiogenic agentsmay be used to promote the remodeling of the blood vessel surroundingthe stent.

In some embodiments, an elastomeric composition or material may be usedto prepare “long term” medical devices. Unlike typical permanent medicaldevices, an elastomeric composition or material will degrade over time.For example, an elastomeric composition or material may be fabricatedinto a biodegradable cardiac stent. In certain embodiments, anelastomeric composition or material is combined with a harder polymerthat plastically forms for the production of stents. Exemplary polymersinclude any of the polymers known in the art, preferably biodegradablepolymers. An elastomeric composition or material may act as aplasticizer that enables the stent to expand into the desired shapeafter implantation. The stent increases the diameter of the blood vesselto allow easier circulation, but, because the stent is biodegradable,surrounding blood vessels increase in diameter without thrombosis orcovering the stent with scar tissue, which would reclose the bloodvessel. The time the stent should remain in place and retain its shapebefore degradation will vary from patient to patient and dependpartially on the amount of blockage and the age of the patient (e.g.,older patients require more time to heal).

In some embodiments, an elastomeric composition or material can be usedas surgical glue. A biocompatible, biodegradable surgical glue may beused to stop bleeding during surgery but does not need to be removedbefore the surgeon sutures the wound closed and will degrade over time.

In some embodiments, an elastomeric composition or material can be usedas a patch for soft tissue defect repair (e.g. closure of defects, suchas vascular defects, cardiac defects, GI defects).

In some embodiments, an elastomeric composition or material can be usedto support in vivo sensors and catheters. It can be constructed into achamber for an optical fiber-based sensor or a coating for a catheterthat is inserted into the area of interest. In a sensor, the chambercontains a specific chromophore-bonded receptor for the molecule ofinterest. When an analyte attaches to the receptor, the chromophore willeither emit or absorb light at an specific wavelength. The absorption oremission may be detected by an apparatus connected to the optical fiber.The sensor may be used for short term, continuous monitoring, forexample, for ten to fifteen days. Likewise, a catheter may be used toperiodically deliver drugs or other small molecules or bioactive agentsto a specific site or intravenously. Use of an elastomeric compositionor material reduces the formation of scar tissue which would ordinarilyform around a shunt or other implant that is used for more than twoweeks. The degradation rate of the bio-rubber should be optimized sothat there is not significant degradation of the material while it is inplace in the patient.

As discussed above, in some embodiments, an elastomeric composition ormaterial comprises an agent for delivery. Such an elastomericcomposition or material can be used in drug delivery. Hydroxyl or aminogroups on an elastomeric composition or material of the presentinvention provide sites to which molecules may be attached to modify thebulk or surface properties of the material. For example, in variousembodiments, tert-butyl, benzyl, or other hydrophobic groups can beadded to the material to reduce the degradation rate. In variousembodiments, polar organic groups such as methoxy can be used tofacilitate adjustment of degradation rate and hydrophilicity. In variousembodiments, addition of hydrophilic groups, for example, sugars, atthese sites can be used to increase the degradation rate.

In various embodiments, acids can be added to an elastomeric compositionor material described here to modify the properties of the material. Forexample, molecules with carboxylic or phosphoric acid groups or acidicsugars can be added. In various embodiments, charged groups such assulfates and amines can be attached to elastomeric compositions andmaterials. Groups that are added to elastomeric compositions andmaterials can be added, for example, via linkage to a freehydroxyl/amino group (substituting for hydrogen), linked directly to thepolymer backbone by substituting for a hydroxyl/amino group,incorporated into an organic group which is linked to elastomericcompositions and materials, and/or incorporated into a cross-link aspart of the link or as a substituent on the link.

In various embodiments, attachment of such non-protein organic orinorganic groups to an elastomeric composition or material can be usedto modify its hydrophilicity and the degradation rate and mechanism. Invarious embodiments, protecting group chemistry can be used to modifythe hydrophilicity of the material.

In various embodiments, to, for example, facilitate controlling and/orregulating material interaction with cells; biomolecules and/orbioactive agents may be coupled to a hydroxyl/amino group or integratedinto the polymer backbone. Association biomolecules and/or bioactiveagents with elastomeric compositions and materials can be conducted inmany ways known in the art. In some embodiments, biomolecules and/orbioactive agents are encapsulated within elastomeric compositions andmaterials. In some embodiments, biomolecules and/or bioactive agents areattached to elastomeric compositions and materials, e.g., covalently,non-covalently, etc. Such attachment can result in a slower releaserate.

In various embodiments of compositions and materials of the presentinventions including one or more biomolecules and/or bioactive agents,the cross-link density of one or more types of cross links is adjustedby adjusting the degree of urethanation, the proportion of one or moreco-polymers, or both, to provide an elastomeric composition or materialthat has a desired biomolecule and/or bioactive agent release rate,release profile, or both.

In various embodiments, for example, biomolecules such as growth factorscan be incorporated into a wound dressing/sealent comprising acomposition or material of the present inventions to recruit cells to awound site and/or promote specific metabolic and/or proliferativebehavior in cells that are at the site and/or seeded within the matrix.Exemplary growth factors include, without limitation, TGF-β, acidicfibroblast growth factor, basic fibroblast growth factor, epidermalgrowth factor, IGF-I and II, vascular endothelial-derived growth factor,bone morphogenetic proteins, platelet-derived growth factor,heparin-binding growth factor, hematopoetic growth factor, and peptidegrowth factor. In various embodiments, integrins and cell adhesionsequences (e.g., the ROD sequence) can be attached to the compositionsand materials of the present inventions to facilitate cell adhesion. Invarious embodiments, extracellular matrix components, e.g., collagen,fibronectin, laminin, elastin, etc., can be combined with compositionsand materials of the present inventions to manipulate cell recruitment,migration, and metabolism and the degradation and mechanical propertiesof the material. In various embodiments, proteoglycans andglycosaminoglycans can be covalently or non-covalently attached tocompositions and materials of the present inventions.

EXEMPLIFICATION

Aspects of the present disclosure may be further understood in light ofthe following examples, which are not exhaustive and which should not beconstrued as limiting the scope of the inventions described here in anyway.

In the following examples, we describe a novel biocompatible andmechanically tunable elastomer, poly (glycerol sebacate urethane)(PGSU). Various elastomeric compositions and materials, in someembodiments, are suitable for efficient encapsulation and controlleddelivery of bioactive macromolecules, and may be applied on cardiac drugdelivery.

Example 1: PGS Pre-Polymer Synthesis

All chemicals were purchased form Sigma-Aldrich (Milwaukee, Wis.) andused as received unless otherwise specified. Poly (glycerol sebacate)(PGS) pre-polymer was synthesized through the polycondensation ofequimolar amounts (0.05 mol) of glycerol and sebacic acid at 120° C. andunder nitrogen atmosphere for 8 hours. The pressure was reduced using anin-house vacuum line and the reaction followed for 16 hours, yielding apale-yellow viscous pre-polymer. The molecular weight was evaluatedusing gel permeation chromatography (Viscotek TDA 305 with Agilent 1260pump and autosampler, Malvern Instruments, Worcestershire, UnitedKingdom). Samples were solubilized in tetrahydrofurane (THF) as solventand eluted through a series of three columns (CLM3010 LT6000L, Malvern)at a flow rate of 1 mL/min Linear polystyrene standards were used forcalibration.

Example 2: Methodology for Preparing PGS Pre-Polymer with Different MWs

The present Example describes methodologies used to prepare exemplaryPGS pre-polymers of different molecular weights.

PGS pre-polymer was synthesized through the polycondensation ofequimolar amounts (0.05 mol) of glycerol and sebacic acid at 120° C. andunder nitrogen atmosphere for 8 hours. The pressure was reduced using anin-house vacuum line and the reactions followed for:

-   -   <13 hours—for a molecular weight bellow 5,000 Da    -   16 hours—for a final molecular weight of around 10,000 Da    -   22 hours—for a final molecular weight about 20,000 Da

It should be understood that the molecular weights indicated above arethose usually observed in reactions under the indicated conditions, butas those skilled in the art variability can occur, for example due tovariations in vacuum intensity or temperature control of the reaction.

It will further be understood that it is not always desirable orpossible to make molecular weight measurements of all samples throughGPC. However, reaction time can be controlled and viscous properties ofproduced pre-polymers can be evaluated. Viscous properties are known tocorrelate to molecular.

Example 3: PGSU Synthesis Using a Solvent-Based Approach (PGSU-S)

To synthesize PGS-urethane (PGSU), after cooling, the PGS pre-polymerwas solubilized in dimethylformamide (DMF, 10% w/v) and heated to 55° C.in the presence of the catalyst stannous 2-ethyl-hexanoate (Tin (II),0.05% w/v). Hexamethylene diisocyanate (HDI) was added dropwise to thereaction mixture. To obtain polymeric films with distinctphysico-chemical properties, different molar ratios of HDI were used(glycerol:HDI—1:1, 1:0.5, 1:0.3). The reaction flask was purged withnitrogen, sealed and the reaction followed for 5 h. The solution wasthen cast on a teflon mold and the solvent allowed to evaporate for 3days at room temperature and 2 days in a vacuum oven at 30° C. to obtainsmooth, non-porous films. Solubility of PGSU-S films was evaluated insolvents including THF, dimethylsulfoxide, dioxane, DMF,dichloromethane.

Example 4: Properties of PGSU Films Prepared Using Solvent BasedMethodology

The present Example describes the impact of various reaction conditionsand components on certain mechanical properties of PGSU films preparedusing solvent-based methodology as described herein.

A—Effect of Molecular Weight

A.1—Molecular Weight Profoundly Impacts Properties

For all the conditions, a constant amount of tin II catalyst (0.1% w/v)was used, and reactions were performed in 10% PGS (w/v) solutions. Itwas observed that a) low MW (below about 5000 Da) pre-polymers do notpermit preparation of PGSU-S with a crosslinking degree of 1:0.3; highercrosslink ratios can be achieved; b) high MW (above about 20,000 Da) donot follow the standard reaction times, especially under conditions ofhigh crosslinking degree (1:1) as it will gel in the flask and do notallow film casting; and c) films do not form with crosslinking ratiosbelow 1:0.3 for the standard Mw of 10,000 Da.

Example 5: PGSU Synthesis Using a Solvent-Free Approach (PGSU-SF)

HDI pre-mixed with Tin(II) (1% v/v) was added to PGS pre-polymer andthoroughly mixed. Several ratios of crosslinking agent were tested(glycerol:HDI—1:1, 1:0.5, 1:0.3). To obtain thin non-porous films,immediately after homogenization, the mixture was spin coated (SCS G3Spin Coater, Specialty Coating systems, Amherst, N.H.) at 3000 RPM for 3minutes on glass coverslips. To facilitate ease of release from theunderlying substrate, the coverslips surface was pre-modified with a(tridecafluoro-1,1,2,2-tetrahydrooctyl)-1-trichlorosilane (Gellest,Morrisville, Pa.). Briefly, after the first spin coating, the materialwas allowed to polymerize for at least 12 hours, followed by spincoating of a second layer directly on the already crosslinked film. Thelayered structure was confirmed by adding a fluorescent dye (rhodamin Band FITC) to each of the layers prior spin coating, followed bymicroscope observation. Elastomeric film thickness could be controlledby the consecutive layering of PGSU-SF or by changing the rotation speedduring the spin coating procedure. Porous scaffolds were fabricatedthrough a foaming process well known for polyurethane materials, withoutrequiring the use of porogens or blowing agents. Briefly, HDI pre-mixedwith Tin(II) (1% v/v) was thoroughly mixed with PGS pre-polymer,followed by casting on a Teflon mold containing grooves (1 cm indiameter and 1 mm in height). The presence of moisture, results in thereaction of HDI with water to form carbon dioxide gas, which diffusesthrough the elastomeric material and creates pores during the curingprocedure. More details can be found in S. Guelcher, A. Srinivasan, A.Hafeman, K. Gallagher, J. Doctor, S. Khetan, S. McBride, J. Hollinger,Tissue Eng. 2007, 13, 2321, which is hereby incorporated by references.

Example 6: Properties of PGSU Films Prepared Using Solvent FreeMethodology

The present Example describes the impact of various reaction conditionsand components on certain mechanical properties of PGSU films preparedusing solvent-free methodology as described herein. PGS having a MW ofapproximately 10,000 were used.

A. Effect of Catalyst

A.1—The absence of catalyst results in non-elastic and stiff PGSU films

-   -   PGSU-SF 1:0.3 prepared through mixing: PGS (100 mg)+HDI (23.8        mg)+Tin II (0.2 uL)    -   PGSU-SF 1:0.3 prepared through mixing: PGS (100 mg)+HDI (23.8        mg)

It was observed that a) patches prepared without Tin(ii) were verybrittle and non-elastic; b) patches prepared with Tin(ii) were elasticand soft; and c) this was the minimum amount of catalyst testedthroughout our experiments.

A.2—Replacement of Tin (II) with DABCO results in non-elastic stiff PGSUfilms

PGSU-SF prepared through mixing: PGS+HDI (23.8 mg)+tin II (0.6 uL)

PGSU-SF prepared through mixing: PGS+HDI (23.8 mg)+DABCO (0.6 uL)

It was observed that a) PGSU patches prepared with tin (ii) were softand elastic; and b) PGSU patches prepared with DABCO were brittle andnon-elastic (similar to when no catalyst was used).

B—Effect of Crosslinker

B.1—Improved Curing with Crosslinker Ratio of at Least 1:0.3

PGSU-SF 1:0.3 prepared through mixing: PGS (100 mg)+HDI (23.8 mg)+tin II(0.2 uL)

PGSU-SF 1:0.2 prepared through mixing: PGS (100 mg)+HDI (15.8 mg)+tin II(0.13 uL)

After mixing, the elastomeric materials were casted on a teflon surface(no spin coating) and crosslining evaluated after 5 hours. It wasobserved that a) PGSU-SF 1:0.2 did not cure, while PGSU-SF 1:0.3 curedwithin a few hours.

C. Effect of Molecular Weight

C.1—Molecular Weight Below about 5000 does not Show Complete Film Curing

Two PGS pre-polymers were tested and molecular weights were determinedthrough GPC. PGS pre-polymer 1 shows Mw=3820; Mn=1684. PGS pre-polymer 2shows Mw=3897; Mn=1594.

-   -   PGSU-SF 1:0.3 prepared through mixing: PGS (100 mg)+HDI (23.8        mg)+tin II (0.2 uL)

The crosslinking was evaluated after 24 hours. Neither of the twopre-polymers with low molecular weights allowed synthesizing filmsshowing not enough crosslink.

C.2—High Molecular Weight PGS Pre-Polymer (>20 000) does not FormUniform Thin Films

We have synthesized several batches with Mw above 20,000 (e.g. Mw=23086,Mn=3068). We could not prepare uniform films using these pre-polymers,as these would gel before allowing easy spreading and spin coating ofthe material. Equivalent amounts of HDI and tin (II) (100 mg of PGS+23.8mg of HDI+0.2 uL of tinII) were used as in previous experiments.

Example 7: Thermally Cured PGS Synthesis

Thermally cured PGS was synthesized as previously described. Briefly,the synthesized PGS pre-polymer was added to a Teflon mold and cured for72 hours at 120° C. and under vacuum. The cured elastomeric material wascarefully removed from the Teflon mold, extracted in absolute ethanolfor 24 hours, dried and stored at −20° C. until further use. Moreexperimental details can be found in Y. D. Wang, G. A. Ameer, B. J.Sheppard, R. Langer, Nat. Biotechnol. 2002, 20, 602, which is herebyincorporated by reference.

Example 8: PGSU Characterization and Discussion

Swelling behavior and sol content of PGSU-S films: Dry polymer disks (4mm in diameter and an average thickness of 0.3 mm, n=5) were weighed(m_(d)) and immersed in 5 mL of ethanol or PBS. After 24 hours, sampleswere removed and, gently wiped and weighed in the swollen state (m_(s)).Swelling percentage was determined according to the formula:Swelling (%)=[(m _(s) −m _(d))/m _(d)]×100

For sol content determination, samples (n=6 per condition) swollen inethanol for 24 hours were dried in an oven at 50° C. until constantweight was achieved. Sol content was determined according to theformula:Sol content (%)=[(m_(i) −m _(f))/m _(i)]×100

Attenuated total reflectance Fourier Transform infrared spectroscopy(ATR-FTIR): ATR-FTIR was performed using a Bruker Alphaspectrophotometer (Billerica, Mass.) to determine the molecularstructure of the PGS pre-polymer and PGSU films.

Differential scanning calorimetry of PGS-S films: Thermal properties ofelastomeric films prepared through the solvent-based method wereevaluated using a differential scanning calorimeter (Perkin ElmerPyris1, Waltham, Mass.): a first cycle was run between −50 and 100° C.to normalize the thermal history of all the samples, followed by asecond cycle in the same temperature range performed at heating andcooling rates of 20° C./min and 40° C./min, respectively. Glasstransition temperature (T_(g)) was measured as the midpoint of theheat-capacity change in the second heating cycle.

Mechanical properties evaluation: Mechanical testing was performed on anADMET eXpert 7601 universal tester (Norwood, Mass.), equipped with a 50Nload cell with dog bone shaped specimens (5 mm×3 mm) with an approximatesample thickness of 0.2 mm. PGSU-S samples were treated for 24 hours inethanol to remove sol content. For PGSU-SF samples, sol content was notremoved as we envision the application of this material for drugdelivery applications, where this step would not be applicable. Allsamples were immersed in phosphate buffer saline (PBS) at 37° C. for 24hours prior testing. Uniaxial tensile testing was performed at a jograte of 50 mm/min until sample failure (n>4 per condition) and Young'smodulus calculated as the slope at 15% strain. Results were compared tothe previously described thermally cured PGS. Cyclical fatigue tensiletesting (n=3) was performed at a jog rate of 50 mm/min, by sampleextension until 30% elongation during 100 consecutive cycles.

In vitro degradation studies of PGSU-S films: In vitro enzymaticdegradation was evaluated using bovine pancreatic cholesterol esterasesolution (40 U/mL) using weighted (m_(i)) dry PGSU discs (4 mm indiameter with an average thickness of 1 mm, n=3 per time point andcondition). Enzyme solution was changed every 24 hours to ensureesterase activity. After each time point, discs were rinsed thoroughlywith double distilled water and dried at 60° C. until constant weight(m_(f)). Remaining mass was calculated using the formula:Remaining mass (%)=[(m _(f) −m _(i))/m _(i)]×100

In vitro biocompatibility of PGSU-S films: Human mesenchymal stem cells(hMSC) were cultured in α-MEM medium supplemented with 15% fetal bovineserum (Atlanta Biologics, Lawrenceville, Ga.), 1% (v/v) L-glutamine, 1%(v/v) penn-strep at 37° C. and 5% CO₂. For all experiments, cellsbetween passage 3 and 6 were used. Glass coverslips with 15 mm diameterwere cleaned with sodium hydroxide solution (10% w/v) followed bysonication with absolute ethanol, drying with nitrogen gas andactivation with oxygen plasma (Harrick Plasma PDC-002, Ithaca, N.Y.) for10 minutes. PGSU-S solutions (10% w/v) were immediately spin coated at1500 RPMs and left to dry at 30° C. until constant weight. Prior to cellseeding, spin-coated cover slips were disinfected under UV for 1 hour,extracted with cell media for 3 hours, washed with PBS and placed intothe wells of 24 well non-tissue culture treated plates. Tissue cultureplastic (TCP) served as a positive control. Cells were seeded at adensity of 2000 cells/cm² with 1mL of growth media per well (n=3 percondition and time point). Media was changed after the first 24 hoursand then every 3 days. At 1, 3, 6 and 8 days, metabolic activity wasevaluated through an MTT assay (Invitrogen, Grand Island, N.Y.)performed according to the vendor protocol and the absorbance read at570 nm using an Epoch microplate reader (BioTek, Winooski, Vt.). Priorto MTT, each well was rinsed with PBS and coated cover slips weretransferred to new wells. At days 1 and 8, phase-contrast microscopepictures were acquired for both polymer and control (TCP) wells using aTE2000-U Inverted Nikon Microscope with a DS-Qi1 monochrome cooleddigital camera.

In vivo biodegradation and biocompatibility of PGSU-S films: Allsurgical procedures were approved by the Institutional Animal Care andUse Committee (IACUC) of the Massachusetts General Hospital andperformed according to the NIH Guidelines for the Care and Use ofLaboratory Animals. All experiments involved the subcutaneousimplantation of polymer discs in adult female Lewis rats (Charles RiverLaboratories, Wilmington, Mass.). Specifically, three 1.5 cm longmidline incisions were made on the back of each animal. Autoclaved andpre-wetted PGSU-S (1:1, 1:0.5, 1:0.3) discs with 10 mm diameter and anaverage thickness of 0.5 mm were implanted subcutaneously in randompositions. As control, PLGA discs with similar dimensions(50:50carboxylate end group, Durect Corporation) were used. At the predefinedtime points (1, 4, 8, 20, 40 weeks), the implants and surrounding tissuewere harvested. For time points 1 and 4 weeks, three replicas permaterial and time point were implanted, while five replicas per materialand per time were used for time points 4, 8, 20 and 40 weeks (n=2 forhistology evaluation, n=3 for weight loss evaluation). Remaining drydisc weight was determined and compared with sample weight priorimplantation. The microscale morphology of implants was evaluatedthrough scanning electron microscopy (SEM, Jeol 5910). Tissue sectionswere prepared and stained with Hematoxylin and Eosin (H&E) and anti-CD68stains.

In vivo cardiac biocompatibility of PGSU-SF films All surgicalprocedures were approved by the IACUC of the Children's Hospital Bostonand performed according to the NIH Guidelines for the Care and Use ofLaboratory Animals Briefly, adult male Wistar rats (Charles RiverLaboratories, Wilmington, Mass.) were anesthetized with anintraperitoneal injection of ketamine (100 mg/kg) and xylazine (10mg/kg), followed by intratracheal intubation. Rats were ventilated witha small animal respirator (Harvard Apparatus, Holliston, Mass.), andanesthesia was maintained with 0.5 to 1.0% isofluorane and 100% oxygen.The heart was accessed through an anterior right-sided thoracotomy,followed by the removal of the pericardial sac. A 1 mm thick and 7 mm indiameter porous PGSU-SF 1:0.3 patch was sutured on the left ventricle(LV) epicardial surface of the rat heart using three 7-0 polypropylenemonofilament stitches. The chest wall was closed in layers, and thethoracic cavity evacuated with a 18-gauge intravenous catheter Animalswere sacrificed at 1 and 4 weeks (n=4 per time point) after the surgicalprocedure with CO₂, followed by immediate excision of the heart. Tissuesections transverse to the patch and heart surface were stained withHematoxylin and Eosin stain (H&E). Echocardiographic analysis (VIVID7,GE Medical Systems, equipped with a 15 MHz probe) was performed prior tosurgical procedures and immediately before animal sacrifice to accesscardiac function.

Protein delivery studies: The incorporation of bioactive molecules inthe PGSU elastomeric material was achieved by mixing the lyophilizedproteins with PGS pre-polymer, followed by the addition of HDI andTin(II) as previously described. For protein bioactivity studies,Lysozyme from chicken egg white (14.3 kDa) was used as a model proteinwith. Polymer discs with encapsulated protein (5 mg per 1 g of PGSpre-polymer) were immersed in 0.5 mL of PBS and incubated at 37° C. (n=4per time point and condition). At defined time points the releasesupernatant was removed and stored at −20° C. until further analysis.The protein release profile was evaluated using a micro-BCA (Pierce,Rockford, Ill.) assay and the amount of active protein released wasevaluated by monitoring the optical density changes of a Micrococcuslysodeikticus lysate solution, according to the vendor's protocol. Forthe controlled release studies, bovine serum albumin (BSA, 66.5 kDa,Millipore, Billerica, Mass.) was used. BSA only, or BSA co-lyophilizedwith trehalose (BSA:Tre, 1:1 mass ratio) were used in this study. Priorto encapsulation, BSA or BSA:Tre powders were sieved through 32 and 75μm pores, to achieve a uniformly sized powder. The ratio of 34 mg of BSAor BSA:Tre to 100 mg of pre-polymer was constant throughout the study.Layers of non-porous PGSU-SF were spin coated. As a proof of concept, athree-layer strategy was used, while alternating the layer(s) where BSAor BSA:Tre was encapsulated. The same release and supernatant storagestrategies were used for this study (n=3 per condition and time point).Differences in the release profile were evaluated through proteinquantification using a micro-BCA assay.

Swelling studies of PGSU-SF films Swelling studies were performed fortrilayered PGSU-SF 1:0.3 films and PGSU-SF containing BSA orBSA-trehalose (1:1) in all the three layers. Loading was 34 mg per 100mg of PGS for both conditions. Polymer disks (6 mm in diameter and anaverage thickness of 0.1 mm, n=3 per condition) were immersed in 5 mL ofPBS. After 24 hours, samples were removed, gently wiped and weighed inthe swollen state (m_(s)). Swollen samples were dried at 50° C. untilconstant weight (m_(d)). Swelling percentage was calculated relativelyto dry mass after swelling according with the previously describedformula.

Statistics All the experiments were repeated at least three times andthe average value was reported. Data are expressed as means±standarddeviation. Statistical analysis was performed using one-way ANOVA withpost hoc Tukey testing to examine statistical difference. Data weretaken to be significant when a P-value of 0.05 or less was obtained.

The PGS pre-polymer used in this study had a weight-average molecularweight of 12700±1600 g/mol and a polydispersity index of 4.5±0.5, asevaluated through gel permeation chromatography. Aliphatichexamethylenediisocyanate (HDI) was chosen as the crosslinker given itslow cost and wide use in the synthesis of biodegradable andbiocompatible polyurethanes. Importantly, PGSU can be synthesized fromthese components through solvent-based (PGSU-S) and solvent-free(PGSU-SF) methods (FIG. 6B). In the solvent-based approach the reactionoccurs in an organic solvent, followed by solvent casting. Afterevaporation, uniform non-porous films with transparent opticalproperties (FIG. 1A) are obtained. To achieve a non-porous elastomersynthesized under solvent-free conditions, after mixing PGS pre-polymerwith the crosslinker, the mixture was spin-coated to achieve a uniformfilm (FIG. 1B) with thickness dependent on the spin coating rate.Several stacked layers can be subsequently spin-coated. A strongentanglement between layers is likely achieved due to the reaction ofHDI with unreacted hydroxyl groups present in the underlying polymerlayer. Porous scaffolds were also fabricated in the absence of organicsolvents through a foaming process, well-known for polyurethanes. Thepresence of moisture results in the reaction of HDI with water to formcarbon dioxide gas, which diffuses through the elastomeric material andcreates pores during the curing process in thicker films (FIG. 1C). ThePGS pre-polymer characteristics dictate the properties of the PGSU-SFfilms obtained: the presence of free hydroxyl groups in the pre-polymerbackbone can be easily crosslinked under mild conditions, while the lowviscosity at temperatures below 37° C. permits uniform mixing with HDIand spin coating to achieve uniform PGSU layers with controllablethickness. PGSU-SF films can be synthesized in under 24 hours, which isa major advantage compared to other elastomers that require long periodsof time for complete polymerization or solvent evaporation.

The reaction efficiency and the molecular structure of the derivativesobtained were evaluated by FTIR (FIG. 6C). The PGS pre-polymer presentsa broad peak at 3445 cm⁻¹, resulting from free hydroxyl groups (—OHstretch). With the addition of HDI, free hydroxyl groups are replaced byurethane groups and consequently a proportional deviation of this peakto lower wavelength (PGSU-S 1:0.3 at 3359 cm⁻¹, PGSU-S 1:0.5 at 3337cm⁻¹, PGSU-S 1:1 at 3329 cm⁻¹) is observed, corresponding to the —NHgroup stretch. This shift also reveals the increase in hydrogen bondingforces with the isocyanate linker content. The peak near 1735 cm⁻¹ isattributed to the carbonyl group stretching from ester groups in PGSpre-polymer and PGSU derivatives. Amide I and amide II bands at 1630 and1580 cm⁻¹ are only observed in PGSU derivatives, further confirming theestablishment of urethane linkages in the polymer backbone. The absenceof the characteristic isocyanate group band at 2270 cm⁻¹ reveals thecomplete reaction of the isocyanate groups in all PGSU derivatives.Similar spectra were obtained for films prepared through thesolvent-free approach, indicating no major chemical differences in thepolymeric network established. All derivatives synthesized wereinsoluble in a variety of organic solvents (e.g. tetrahydrofuran,dimethylsulfoxide, dioxane, DMF, dichloromethane), further confirmingthe establishment of an interchain chemically crosslinked network.

Thermal properties were evaluated for PGSU-S films, with all derivativesshowing glass transition temperature (T_(g)) values below 0° C. (−11.8°C. for PGSU-S 1:0.3, −7.3° C. for PGSU-S 1:0.5, −4.2° C. for PGSU-S1:1). The material's amorphous nature at room and body temperatureassures it elastomeric properties. In addition, the lack ofsignificative swelling of PGSU films in physiological solutions (FIG. 2) also contributes to its mechanical integrity once exposed to a wetenvironment (e.g. in vivo). The high degree of swelling in ethanol (FIG.2 ) facilitates the removal of any unreacted monomers (sol content)entangled in the crosslinked network.

Several strategies have been previously reported to improve themechanical properties of PGS elastomers, including the addition ofmicron-size fillers (e.g. Bioglass), or the introduction of novelfunctional groups (e.g. amide groups) to improve the polymercrosslinking. Despite considerable improvements in the range ofproperties achieved, high curing temperatures are still required.Through simply changing the degree of crosslinking introduces by theurethane groups, PGSU films can be tailored to achieve a broad range ofmechanical properties (Young's modulus from 0.1 to 20 MPa,approximately), mimicking the stiffness of a diverse range of tissues,such as the myocardium, pericardium, skin, aorta, or cartilage (FIGS. 6Cand 6D). Also of interest is the improved tensile strength of PGSU filmscompared to thermally cured PGS. For example, both PGSU-S and -SF 1:0.3and PGS show a Young's modulus bellow 1 MPa but, the urethane crosslinkimproves the tensile strength (1.35±0.76 MPa for PGSU-S 1:0.3, 0.38±0.06MPa for PGS) and elongation (516±109% for PGSU-S 1:0.3, 200±30% for PGS)properties of the material. These features may be exploited inload-bearing applications where strength and elasticity are essential.Furthermore, biomaterials are often significantly manipulated prior toproper placement and thus must maintain their integrity not onlyfollowing transplantation but also during surgical implantation. Towardsthis end, PGSU also shows a favorable behavior when exposed tocontinuous cyclical loadings, presenting minimal creep deformation andminimal loss of tensile strength after 100 tensile cycles (FIG. 6F). Thepresence of covalent crosslinks between the polymeric chains likelyprevents them from sliding past one another, therefore improving theirstability under dynamic environments. In comparison, aliphaticpolyurethanes have been associated with permanent deformation onceexposed to tensile forces.

To determine the potential of PGSU derivatives in biomedicalapplications, we assessed their biodegradation profiles andcytocompatibility in vitro. In the presence of cholesterol esterase,PGSU-S films exhibited a degradation profile dependent on the degree ofcrosslinking (FIG. 3 ). The ester groups in the polymer backbone arehighly sensitive to enzymatic degradation; however, with increasedurethane content the accessibility to ester bonds is hindered resultingin slower degradation rates. Human mesenchymal stem cells were used totest the cytocompatibility of PGSU-S materials. Cells adhered to PGSU-Sfilms at lower extent than tissue culture polystyrene (TCP) (day 1);however, they were able to proliferate and at day 8 their metabolism, asassessed by a MTT assay, was not statistical different in both cultureconditions (FIGS. 4A-4C). Given the positive preliminary data, weexamined the in vivo acute and chronic inflammatory response in asubcutaneous rat animal model and compared with poly(lactic-co-glycolicacid) (PLGA), an FDA-approved material for several internalapplications. PLGA samples were only visible during harvesting at 1week, as all samples were nearly fully degraded at 4 weekpost-implantation. No adverse reactions to the implants or complicationswere noted during the implantation period. H&E and anti-CD68 macrophagestainings were employed to characterize the inflammatory response to theimplantes (FIG. 7A). The inflammatory responses to the PGSU-S wassimilar when comparing all derivatives, and characterized as mixedlymphohistiocytic reaction with predominance of histiocytic at 1 and 4week time points and lymphocytic reaction at all later time points. Nogiant cells could be identified in any material group at any time point.All PGSU sample groups exhibited mild to moderate infiltration byCD68-positive macrophages at 1 wk post implantation; at all later timepoints, CD68-positive infiltration was characterized as mostly minimalThe inflammatory reaction to PLGA was significantly higher (p<0.5) at 1and 4 weeks than the reaction to the PGSU-S (FIG. 7B). Capsule thicknessdid not vary significantly among all samples (FIG. 7B), and wasconsiderably thinner when comparing with other previously describedelastomers.

Following 20 weeks of implantation, all samples maintained theircircular shape, with PGSU-S 1:0.3 and 0.5 exhibiting a gradual decreasein sample diameter and thickness, with a remaining weight of 59.9±3.9and 68.2±1.5%, respectively (FIG. 7C). At week 40, explanted PGSU-S1:0.3 and PGSU-S 1:0.5 samples were broken and therefore not consideredfor weight loss evaluation. The degradation rate observed for all thederivatives is slower than what has been described for other elastomers,such as PGS whose degradation rate cannot be tuned. SEM evaluation ofPGSU-S 1:0.3 following 20 weeks showed minimal morphological changes onthe micron-scale suggesting that the degradation mechanism is based onsurface erosion (FIG. 6D). No significant weight loss or morphologicchanges were observed for PGSU-S 1:1 samples during the 40 week study.

One of the areas where biodegradable elastomers are gaining muchattention is cardiac therapy, with potential applications ranging fromreconstructive procedures, tissue engineering to localized drugdelivery. Previous studies demonstrated that the mechanical complianceand degradation properties of biomaterials applied to the heart stronglyinfluence cardiac function and the material's integration with the hosttissue. However, clinically-used materials (e.g., Dacron) are stiff,non-degradable and are associated with long-term fibrosis andcalcification, compromising regional function. Porous PGSU-SF 1:0.3exhibits similar mechanical properties to native heart tissue and, giventhe mild synthetic conditions, may allow localized delivery of bioactivemacromolecules. Such an approach may provide new therapeutic options forcardiac disease given that many biomolecules exhibit short half-livesand/or present systemic toxicity. Towards potential cardiacapplications, we performed a preliminary in vivo biocompatibility studyto evaluate how porous PGSU-SF 1:0.3 interacts with myocardial tissue.Specifically, PGSU-SF films could be easily manipulated and sutured,showing excellent tear-resistant properties. Cardiac acute and chronicinflammatory responses to PGSU-S 1:0.3 films were evaluated one and fourweek after surgery, respectively, through H&E staining (FIG. 6E). Whilediffuse granulation tissue and infiltrated lymphocytes were visiblesurrounding the implant, the myocardial surface did not show signs of asignificant inflammatory response and no major fibrotic response orcollagen deposition was observed. No changes in cardiac function wereobserved via echocardiography analysis (FIG. 6F). Moderate chestadhesions, common following thoracotomy procedures, were observed duringheart excision at both time points.

Given the possibility of preparing PGSU-SF elastomers under mildconditions, we evaluated its applicability as a controlled deliverysystem of bioactive molecules. While the use of polyurethane foams forthe delivery of therapeutic proteins has been previously reported, themechanical properties of the materials obtained have been limited totensile moduli bellow 0.12 MPa. In contrast, proteins could easily beloaded directly into the highly tunable PGSU-SF, without interferingwith the curing process or final properties of the elastomer. Toevaluate the bioactivity of the released biomolecules, lysozyme was usedas a model protein, given the availability of simple and cost-effectiveassays to quantify its activity. The protein was encapsulated in porousPGSU-SF and exhibited a small burst during the first 48 hours, followedby sustained protein release for at least 5 days (data not shown).Importantly, the majority of the protein released was bioactive (FIG.8A).

Next, to achieve tighter control over the delivery profile, we developeda strategy based on the sequential layering of PGSU-SF, allowing finecontrol over the localization of the encapsulated molecules (FIG. 8B).When the pre-polymer is spin coated at 3000 RPM and without proteinpowder, the size of each layer is 33.5±0.1 μm. Given that the release isbased on diffusion and polymer degradation mechanisms, controlledrelease could be achieved through altering the stacking order ofprotein-loaded and unloaded layers, the size of the encapsulated proteinpowder, and the presence of osmotic agents. As proof of concept, thelyophilized model protein Bovine Serum Protein (BSA) was sieved toparticle sizes bellow 32 μm, similar to the thickness of each layer, and75 μm. These were encapsulated in internal layers of PGSU-SF 1:0.3films. Given the low swelling in aqueous solution of PGSU films, themajority of the protein is entrapped in the polymeric network,especially when the particle size is smaller than the layer thickness(FIG. 8C). The use of particles of bigger size results in increasedprotein release at earlier time points given the proximity to thepolymer surface. This might promote a porous structure that furthercontributes the sustained release of protein for longer periods of time.The release efficiency could be improved through the co-encapsulation ofBSA with an osmotic agent, trehalose, by improving the water uptake fromPGSU-SF films (FIGS. 5A and 5B). The encapsulation of BSA-trehalosesieved to small particle size in internal PGSU-SF layers resulted withsustained protein release for more than 18 days, with almost 50% of thetotal loading released (FIG. 8D). The encapsulation of the sameformulation in external polymer layers results in faster release of theprotein loaded. These preliminary results demonstrate the versatility ofPGSU-SF materials, which can be selectively modulated to achieve highlyspecific release kinetics through simple changes in the filmspreparation methods.

Equivalents

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. The scope of the presentinvention is not intended to be limited to the above Description, butrather is as set forth in the following claims:

We claim:
 1. A composition comprising : a polyester material, thematerial comprising a plurality of A and B components, wherein the A andB components form a plurality of polymeric backbones formed of (-A-B-)repeat units, having the general formula (-A-B-)_(p), wherein: p is aninteger greater than 1; the (-A-B-) repeat units have a chemicalstructure produced by condensation of a polyol component A′ with apolyacid component B; the A component of at least two of the (-A-B-)repeat units within each of the polymeric backbones has at least onefree hydroxyl group present thereon, prior to crosslinking; apolyisocyanate crosslinker; wherein the at least one free hydroxyl groupto the polyisocyanate crosslinker is present at a molar ratio of betweenabout 1:0.2 and about 1:0.8 or between about 1:1.2 and about 1:1.5; andwherein the polyester material crosslinked by the polyisocyanatecrosslinker is an elastomeric polyester material cross-linked by aplurality of urethane cross-links which covalently link the polymericbackbones between the A components of the at least two (-A-B-) repeatunits within each of the polymeric backbones.
 2. The composition ofclaim 1, wherein the polyester material has a molecular weight betweenabout 3,000 and about 25,000 Daltons.
 3. The composition of claim 1,wherein the polyol component A′ is selected from the group consisting ofglycerol, erythritol, threitol, ribitol, arabinitol, xylitol, allitol,altritol, galactritol, sorbitol, mannitol, iditol, lactitol, isomalt,and maltitol.
 4. The composition of claim 1, wherein the polyacidcomponent B′ is selected from the group consisting of sebacic acid,succinic acid, fumaric acid, α-ketoglutaric acid, oxaloacetic acid,malic acid, oxalosuccinic acid, isocitric acid, cis-aconitic acid,citric acid, 2-hydroxy-malonic acid, tartaric acid, ribaric acid,arabanaric acid, xylaric acid, allaric acid, altraric acid, galactericacid, glucaric acid, or mannaric acid, dimercaptosuccinic acid, oxalicacid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelicacid, suberic acid, and azelaic acid.
 5. An elastomeric cross-linkedpolyester material comprising: a plurality of A and B components,wherein the A and B components form a plurality of polymeric backbonesformed of (-A-B-) repeat units, having the general formula (-A-B-)_(p),wherein: p is an integer greater than 1; the (-A-B-) repeat units have achemical structure produced by condensation of a polyol component A′with a polyacid component B′; and wherein the A component of at leasttwo of the (-A-B-) repeat units within each of the polymeric backboneshas at least one free hydroxyl group present thereon, prior tocrosslinking; wherein crosslinking is carried out by a polyisocyanatecrosslinker and the at least one free hydroxyl group to thepolyisocyanate crosslinker is at a molar ratio of between about 1:0.2and about 1:0.8 or between about 1:1.2 and about 1:1.5; and wherein aplurality of urethane cross-links covalently crosslink the polymericbackbones between the A components of the at least two (-A-B-) repeatunits within each of the polymeric backbones.
 6. The elastomericcross-linked polyester material of claim 5, wherein the elastomericpolyester material crosslinked by the plurality of urethane cross-linkshas one or more properties selected from the group consisting of: aYoung's modulus of between about 0.5 MPa and about 30 MPa; a tensilestrength of between about 0.5 MPa and about 15 MPa; an elongation ofbetween about 50% and about 600%; a size deformation of below about 20%of its initial length, after tensile loading; a tensile strength stablewithin about 5% to about 30% of the initial strength over 100 cycles ofextension; a size deformation stable within about 5% to about 30% of theinitial length over 100 cycles of extension; and combinations thereof.7. The elastomeric cross-linked polyester material of claim 5, whereinthe polyol component A′ is glycerol and the polyacid component B′ issebacic acid.
 8. The elastomeric cross-linked polyester material ofclaim 5, wherein the elastomeric cross-linked polyester material has amolecular weight between about 3,000 and about 25,000 Daltons.
 9. Theelastomeric cross-linked polyester material of claim 5, wherein theelastomeric cross-linked polyester material is free of solvent.
 10. Theelastomeric cross-linked polyester material of claim 5, furthercomprising a porogen.
 11. The elastomeric cross-linked polyestermaterial of claim 5, wherein the elastomeric cross-linked polyestermaterial further comprises one or more agents selected from the groupconsisting of: therapeutic agents, cytotoxic agents, diagnostic agents,prophylactic agents, nutraceutical agents, and combinations thereof. 12.The elastomeric cross-linked polyester material of claim 5 in the formof a patch.
 13. The elastomeric cross-linked polyester material of claim12, wherein the patch comprises a light activatable adhesive.
 14. Theelastomeric cross-linked polyester material of claim 12, wherein thepatch is a medical patch for repair of a soft tissue defect.
 15. Theelastomeric cross-linked polyester material of claim 14, wherein thesoft tissue defect is a tissue closure defect, a vascular defect, acardiac defect, or a gastrointestinal defect.
 16. A method of making theelastomeric cross-linked polyester material of claim 5 comprising thesteps of: providing a polyester material, the polyester materialcomprising a plurality of A and B components, wherein the A and Bcomponents form a plurality of polymeric backbones formed of (-A-B-)repeat units having the general formula (-A-B-)_(p), wherein: p is aninteger greater than 1; the (-A-B-) repeat units have a chemicalstructure formed when a polyol component A′ is condensed with a polyacidcomponent B; at least two of the (-A-B-) repeat units within each of thepolymeric backbones have at least one free hydroxyl group presentthereon on the A component of the at least two (-A-B-) repeat unitswithin the polymeric backbones; and mixing the polyester material with apolyisocyanate crosslinker, wherein the at least one free hydroxyl groupand the polyisocyanate crosslinker are at a molar ratio of between about1:0.2 and about 1:0.8 or between about 1:1.2 and about 1:1.5, such thatthe elastomeric urethane cross-linked polyester material comprising aplurality of urethane crosslinks is produced; and wherein the urethanecrosslinks covalently crosslink the polymeric backbones between the Acomponents of the at least two (-A-B-) repeat units within each of thepolymeric backbones.
 17. The method of claim 16, wherein the step ofmixing is conducted in the presence of at least one solvent.
 18. Themethod of claim 16, wherein the step of mixing is conducted in theabsence of solvent.
 19. The method of claim 16, wherein the step ofmixing is conducted at a temperature less than 60° C.
 20. The method ofclaim 16, wherein the step of mixing is conducted at room temperature.